Polynucleotides encoding a novel interleukin receptor termed interleukin-17 receptor-like protein

ABSTRACT

The present invention relates to a novel IL17RLP protein which is a member of the interleukin (IL)-17 receptor family. In particular, isolated nucleic acid molecules are provided encoding the human IL17RLP protein. IL17RLP polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of IL17RLP activity. Also provided are diagnostic methods for detecting immune system-related disorders and therapeutic methods for treating immune system-related disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a division of U.S. application Ser. No.09/154,219, filed Sep. 16, 1998, which claims benefit under 35 U.S.C. §119(e) of the filing date of copending U.S. Provisional ApplicationSerial No. 60/059,133, filed on Sep. 17, 1997, wherein each of theabove-identified applications is hereby incorporated herein by referencein its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a novel human gene encoding apolypeptide which is a member of the interleukin (IL)-17 receptorfamily. More specifically, isolated nucleic acid molecules are providedencoding a human polypeptide named Interleukin 17-Receptor-Like Protein,hereinafter referred to as IL17RLP. IL17RLP polypeptides are alsoprovided, as are vectors, host cells and recombinant methods forproducing the same. Also provided are diagnostic methods for detectingdisorders related to the immune system and therapeutic methods fortreating such disorders. The invention further relates to screeningmethods for identifying agonists and antagonists of IL17RLP activity.

BACKGROUND OF THE INVENTION

[0003] Cytokines typically exert their respective biochemical andphysiological effects by binding to specific receptor molecules.Receptor binding will then stimulate specific signal transductionpathways (Kishimoto, T., et al., Cell 76:253-262 (1994). The specificinteractions of cytokines with their receptors are often the primaryregulators of a wide variety of cellular process including activation,proliferation, and differentiation (Arai, K.-I, et al., Ann. Rev.Biochem. 59:783-836 (1990); Paul, W. and Seder, R., Cell 76:241-251(1994)).

[0004] Human interleukin (IL)-17 was only recently identified. IL-17 isa 155 amino acid polypetide which was molecularly cloned from a CD4+T-cell cDNA library (Yao, Z., et al., J. Immunol. 155:5483-5486 (1995)).The IL-17 polypeptide contains an N-terminal signal peptide and containsapproximately 72% identity at the amino acid level with a T-cell trophicherpesvirus saimiri (HVS) gene designated HVS13. High levels of IL-17are secreted from CD4-positive primary peripheral blood leukocytes (PBL)upon stimulation (Yao, Z., et al., Immunity 3:811-821 (1995)). Treatmentof fibroblasts with IL-17, HVS13, or another murine homologue,designated CTLA8, activate signal transduction pathways and result inthe stimulation of the NF-κB transcription factor family, the secretionof IL-6, and the costimulation of T-cell proliferation (Yao, Z., et al.,Immunity 3:811-821 (1995)).

[0005] An HVS13-Fc fusion protein was used to isolate a murine IL-17receptor molecule which does not appear to belong to any of thepreviously described cytokine receptor families (Yao, Z., et al.,Immunity 3:811-821 (1995)). The murine IL-17 receptor (mIL-17R) ispredicted to encode a type I transmembrane protein of 864 amino acidswith an apparent molecular mass of 97.8 kDa. mIL-17R is predicted topossess an N-termninal signal peptide with a cleavage site betweenalanine-31 and serine-32. The molecule also contains a 291 amino acidextracellular domain, a 21 amino acid transmembrane domain, and a 521amino acid cytoplasmic tail. A soluble recombinant IL-17R moleculeconsisting of 323 amino acids of the extracellular domain of IL-17Rfused to the Fc portion of human IgG1 was able to significantly inhibitIL-17-induced IL-6 production by murine NIH-3T3 cells (supra).

[0006] Interestingly, the expression of the IL-17 gene is highlyrestricted. It is typically observed primarily in activated T-lymphocytememory cells (Broxmeyer, H. J. Exp. Med. 183:2411-2415 (1996); Fossiez,F., et al., J. Exp. Med. 183:2593-2603 (1996)). Conversely, the IL-17receptor appears to be expressed in a large number of cells and tissuesincluding (Rouvier, E., et al., J. Immunol. 150:5445-5456 (1993); Yao,Z., et al., J. Immunol. 155:5483-5486 (1995)). It remains to be seen,however, if IL-17 itself can play an autocrine role in the expression ofIL-17. IL-17 has been implicated as a causitive agent in the expressionof IL-6, IL-8, G-CSF, Prostaglandin E (PGE₂), and intracellular adhesionmolecule (ICAM)-1 (Fossiez, F., supra; Yao, Z., et al., Immunity3:811-821 (1995)). Each of these molecules possesses highly relevent andpotentially therapeutically valuable properties. For instance, IL-6 isinvolved in the regulation of hematopoietic stem and progenitor cellgrowth and expansion (Ikebuchi, K., et al., Proc. Natl. Acad. Sci. USA84:9035-9039 (1987); Gentile, P. and Broxmeyer, H. E. Ann. N.Y. Acad.Sci. USA 628:74-83 (1991)). IL-8 exhibits a myelosuppressive activityfor stem and immature subsets of myeloid progenitors (Broxmeyer, H. E.,et al., Ann. Hematol. 71:235-246 (1995); Daly, T. J., et al., J. Biol.Chem. 270:23282-23292 (1995)). G-CSF acts early and late to activate andstimulate hematopoiesis in general (more specifically, neutrophilhematopoiesis) while PGE₂ enhances erythropoiesis, suppresseslymphopoiesis and myelopoiesis in general, and strongly suppressesmonocytopoiesis (Broxmeyer, H. E. Amer. J. Ped. Hematol./Oncol. 14:22-30(1992); Broxmeyer, H. E. and Williams, D. E. CRC Crit. Rev.Oncol./Hematol. 8:173-226 (1988)).

[0007] IL-17 receptor appears to be structurally unrelated to anypreviously described cytokine receptor family. Despite the existence of12 cysteine residues in the extracellular domain, their relativepositions are not characteristic of receptor molecules classified asmembers of the immunoglobulin superfamily (Williams, A. and Barclay, A.Annu. Rev. Immunol. 6:381-405 (1988)), the TNFR family (Smith, C., etal., Science 248:1019-1023 (1990)), the hematopoietin receptor family(Cosman, D. Cytokine 5:95-106 (1993)), or any previously describedtyrosine kinase receptors (Hanks, S., et al., Science 241:42-52 (1988)).

[0008] Thus, there is a need for polypeptides that function as receptormolecules for cytokines and, thereby, function in the transfer of anextracellular signal ultimately to the nucleus of the cell, sincedisturbances of such regulation may be involved in disorders relating tocellular activation, hemostasis, angiogenesis, tumor metastasis,cellular migration and ovulation, as well as neurogenesis. Therefore,there is a need for identification and characterization of such humanpolypeptides which can play a role in detecting, preventing,ameliorating or correcting such disorders.

SUMMARY OF THE INVENTION

[0009] The present invention provides isolated nucleic acid moleculescomprising a polynucleotide encoding at least a portion of the IL17RLPpolypeptide having the complete amino acid sequence shown in SEQ ID NO:2or the complete amino acid sequence encoded by the cDNA clone depositedas plasmid DNA as ATCC Deposit Number 209198 on Aug. 8, 1997. Thenucleotide sequence determined by sequencing the deposited IL17RLPclone, which is shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1), contains anopen reading frame encoding a complete polypeptide of 426 amino acidresidues, including an initiation codon encoding an N-terminalmethionine at nucleotide positions 10-12, and a predicted molecularweight of about 47.1 kDa. Nucleic acid molecules of the inventioninclude those encoding the complete amino acid sequence excepting theN-terminal methionine shown in SEQ ID NO:2, or the complete amino acidsequence excepting the N-terminal methionine encoded by the cDNA clonein ATCC Deposit Number 209198, which molecules also can encodeadditional amino acids fused to the N-terminus of the IL17RLP amino acidsequence.

[0010] The encoded polypeptide has a predicted leader sequence of 19amino acids underlined in FIGS. 1A, 1B, and 1C; and the amino acidsequence of the predicted mature IL17RLP protein is also shown in FIGS.1A, 1B, and 1C as amino acid residues 20-426, and as residues 1-407 inSEQ ID NO:2.

[0011] Thus, one aspect of the invention provides an isolated nucleicacid molecule comprising a polynucleotide comprising a nucleotidesequence selected from the group consisting of: (a) a nucleotidesequence encoding the IL17RLP polypeptide having the complete amino acidsequence in SEQ ID NO:2 (i.e., positions −19 to 407 of SEQ ID NO:2); (b)a nucleotide sequence encoding the IL17RLP polypeptide having thecomplete amino acid sequence in SEQ ID NO:2 excepting the N-terminalmethionine (i.e., positions −18 to 407 of SEQ ID NO:2); (c) a nucleotidesequence encoding the predicted mature IL17RLP polypeptide having theamino acid sequence at positions 1 to 407 in SEQ ID NO:2; (d) anucleotide sequence encoding a polypeptide comprising the predictedextracellular domain of the IL17RLP polypeptide having the amino acidsequence at positions 1 to 271 in SEQ ID NO:2; (e) a nucleotide sequenceencoding a soluble IL17RLP polypeptide having the predictedextracellular and intracellular domains, but lacking the predictedtransmembrane domain; (f) a nucleotide sequence encoding the IL17RLPpolypeptide having the complete amino acid sequence encoded by the cDNAclone contained in ATCC Deposit No. 209198; (g) a nucleotide sequenceencoding the IL17RLP polypeptide having the complete amino acid sequenceexcepting the N-terminal methionine encoded by the cDNA clone containedin ATCC Deposit No. 209198; (h) a nucleotide sequence encoding themature IL17RLP polypeptide having the amino acid sequence encoded by thecDNA clone contained in ATCC Deposit No. 209198; (i) a nucleotidesequence encoding the extracellular domain of the IL17RLP polypeptidehaving the amino acid sequence encoded by the cDNA clone contained inATCC Deposit No. 209198; and (j) a nucleotide sequence complementary toany of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g),(h) or (i) above.

[0012] Further embodiments of the invention include isolated nucleicacid molecules that comprise a polynucleotide having a nucleotidesequence at least 90% identical, and more preferably at least 95%, 96%,97%, 98% or 99% identical, to any of the nucleotide sequences in (a),(b), (c), (d), (e), (f), (g), (h) or (i), above, or a polynucleotidewhich hybridizes under stringent hybridization conditions to apolynucleotide in (a), (b), (c), (d), (e), (f), (g), (h) or (i), above.This polynucleotide which hybridizes does not hybridize under stringenthybridization conditions to a polynucleotide having a nucleotidesequence consisting of only A residues or of only T residues. Anadditional nucleic acid embodiment of the invention relates to anisolated nucleic acid molecule comprising a polynucleotide which encodesthe amino acid sequence of an epitope-bearing portion of a IL17RLPpolypeptide having an amino acid sequence in (a), (b), (c), (d), (e),(f), (g) or (h), above.

[0013] An additional nucleic acid embodiment of the invention relates toan isolated nucleic acid molecule comprising a polynucleotide whichencodes the amino acid sequence of an epitope-bearing portion of aIL17RLP polypeptide having an amino acid sequence in (a), (b), (c), (d),(e), (f) or (g), above. A further embodiment of the invention relates toan isolated nucleic acid molecule comprising a polynucleotide whichencodes the amino acid sequence of a IL17RLP polypeptide having an aminoacid sequence which contains at least one amino acid substitution, butnot more than 50 amino acid substitutions, even more preferably, notmore than 40 amino acid substitutions, still more preferably, not morethan 30 amino acid substitutions, and still even more preferably, notmore than 20 amino acid substitutions. Of course, in order ofever-increasing preference, it is highly preferable for a polynucleotidewhich encodes the amino acid sequence of a IL17RLP polypeptide to havean amino acid sequence which contains not more than 10, 9, 8, 7, 6, 5,4, 3, 2 or 1 amino acid substitutions. Conservative substitutions arepreferable.

[0014] The present invention also relates to recombinant vectors, whichinclude the isolated nucleic acid molecules of the present invention,and to host cells containing the recombinant vectors, as well as tomethods of making such vectors and host cells and for using them forproduction of IL17RLP polypeptides or peptides by recombinanttechniques.

[0015] In accordance with a further aspect of the present invention,there is provided a process for producing such polypeptide byrecombinant techniques comprising culturing recombinant prokaryoticand/or eukaryotic host cells, containing an IL17RLP nucleic acidsequence, under conditions promoting expression of said protein andsubsequent recovery of said protein.

[0016] The invention further provides an isolated IL17RLP polypeptidecomprising an amino acid sequence selected from the group consisting of:(a) the amino acid sequence of the full-length IL17RLP polypeptidehaving the complete amino acid sequence shown in SEQ ID NO:2 (i.e.,positions −19 to 407 of SEQ ID NO:2); (b) the amino acid sequence of thefull-length IL17RLP polypeptide having the complete amino acid sequenceshown in SEQ ID NO:2 excepting the N-terminal methionine (i.e.,positions −18 to 407 of SEQ ID NO:2); (c) the amino acid sequence of themature IL17RLP polypeptide having the complete amino acid sequence shownin SEQ ID NO:2 (i.e., positions 1 to 407 of SEQ ID NO:2); (d) the aminoacid sequence of the predicted extracellular domain of the IL17RLPpolypeptide having the complete amino acid sequence shown in SEQ ID NO:2(i.e., positions 1 to 271 of SEQ ID NO:2); (e) the amino acid sequenceof a soluble IL17RLP polypeptide having the predicted extracellular andintracellular domains, but lacking the predicted transmembrane domain;(f) the complete amino acid sequence encoded by the cDNA clone containedin the ATCC Deposit No. 209198; (g) the complete amino acid sequenceexcepting the N-terminal methionine encoded by the cDNA clone containedin the ATCC Deposit No. 209198; (h) the complete amino acid sequence ofthe mature IL17RLP encoded by the cDNA clone contained in the ATCCDeposit No. 209198, and; (i) the complete amino acid sequence of theextracellular domain of the IL17RLP encoded by the cDNA clone containedin the ATCC Deposit No. 209198. The polypeptides of the presentinvention also include polypeptides having an amino acid sequence atleast 80% identical, more preferably at least 90% identical, and stillmore preferably 95%, 96%, 97%, 98% or 99% identical to those describedin (a), (b), (c), (d), (e), (f), (g), (h) or (i) above, as well aspolypeptides having an amino acid sequence with at least 90% similarity,and more preferably at least 95% similarity, to those above.

[0017] An additional embodiment of this aspect of the invention relatesto a peptide or polypeptide which comprises the amino acid sequence ofan epitope-bearing portion of a IL17RLP polypeptide having an amino acidsequence described in (a), (b), (c), (d), (e), (f), (g), (h) or (i),above. Peptides or polypeptides having the amino acid sequence of anepitope-bearing portion of an IL17RLP polypeptide of the inventioninclude portions of such polypeptides with at least six or seven,preferably at least nine, and more preferably at least about 30 aminoacids to about 50 amino acids, although epitope-bearing polypeptides ofany length up to and including the entire amino acid sequence of apolypeptide of the invention described above also are included in theinvention.

[0018] A further embodiment of the invention relates to a polypeptidewhich comprises the amino acid sequence of an IL17RLP polypeptide havingan amino acid sequence which contains at least one amino acidsubstitution, but not more than 50 amino acid substitutions, even morepreferably, not more than 40 amino acid substitutions, still morepreferably, not more than 30 amino acid substitutions, and still evenmore preferably, not more than 20 amino acid substitutions. Of course,in order of ever-increasing preference, it is highly preferable for apeptide or polypeptide to have an amino acid sequence which comprisesthe amino acid sequence of an IL17RLP polypeptide, which contains atleast one, but not more than 20, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 aminoacid substitutions. In specific embodiments, the number of additions,substitutions, and/or deletions in the amino acid sequence of FIGS. 1A,1B, and 1C, or fragments thereof (e.g., the mature form and/or otherfragments described herein), is 1-5, 5-10, 5-25, 5-50, 10-50, 50-150,50-200 or 100-250, conservative amino acid substitutions are preferable.

[0019] In another embodiment, the invention provides an isolatedantibody that binds specifically to a IL17RLP polypeptide having anamino acid sequence described in (a), (b), (c), (d), (e), (f), (g), (h)or (i) above. The invention further provides methods for isolatingantibodies that bind specifically to a IL17RLP polypeptide having anamino acid sequence as described herein. Such antibodies are usefuldiagnostically or therapeutically as described below.

[0020] The invention also provides for pharmaceutical compositionscomprising IL17RLP polypeptides, particularly human IL17RLPpolypeptides, which may be employed, for instance, to treat disordersrelating to cellular activation, hemostasis, angiogenesis, tumormetastasis, cellular migration and ovulation, as well as neurogenesis.Methods of treating individuals in need of IL17RLP polypeptides are alsoprovided.

[0021] The invention further provides compositions comprising an IL17RLPpolynucleotide or an IL17RLP polypeptide for administration to cells invitro, to cells ex vivo and to cells in vivo, or to a multicellularorganism. In certain particularly preferred embodiments of this aspectof the invention, the compositions comprise an IL17RLP polynucleotidefor expression of an IL17RLP polypeptide in a host organism fortreatment of disease. Particularly preferred in this regard isexpression in a human patient for treatment of a dysfunction associatedwith aberrant endogenous activity of an IL17RLP polypeptide.

[0022] The present invention also provides a screening method foridentifying compounds capable of enhancing or inhibiting a biologicalactivity of the IL17RLP polypeptide, which involves contacting a ligandwhich is inhibited by the IL17RLP polypeptide with the candidatecompound in the presence of an IL17RLP polypeptide, assayingreceptor-binding activity of the ligand in the presence of the candidatecompound and of IL17RLP polypeptide, and comparing the ligand activityto a standard level of activity, the standard being assayed when contactis made between the ligand itself in the presence of the IL17RLPpolypeptide and the absence of the candidate compound In this assay, anincrease in ligand activity over the standard indicates that thecandidate compound is an agonist of IL17RLP activity and a decrease inligand activity compared to the standard indicates that the compound isan antagonist of IL17RLP activity.

[0023] In another aspect, a screening assay for agonists and antagonistsis provided which involves determining the effect a candidate compoundhas on IL17RLP binding to a ligand. In particular, the method involvescontacting the ligand with an IL17RLP polypeptide and a candidatecompound and determining whether IL17RLP polypeptide binding to theligand is increased or decreased due to the presence of the candidatecompound. In this assay, an increase in binding of IL17RLP over thestandard binding indicates that the candidate compound is an agonist ofIL17RLP binding activity and a decrease in IL17RLP binding compared tothe standard indicates that the compound is an antagonist of IL17RLPbinding activity.

[0024] It has been discovered that IL17RLP is expressed not only inadult pulmonary tissue, but also in Crohn's Disease tissue, kidneypyramid, cortex, and medulla tissues, hippocampus, frontal cortex of thebrain from a patient with epilepsy, adrenal gland tumor, striatumdepression, osteclastoma, endometrial tumor, and hypothalamus from apatient with Schizophrenia. Therefore, nucleic acids of the inventionare useful as hybridization probes for differential identification ofthe tissue(s) or cell type(s) present in a biological sample. Similarly,polypeptides and antibodies directed to those polypeptides are useful toprovide immunological probes for differential identification of thetissue(s) or cell type(s). In addition, for a number of disorders of theabove tissues or cells, particularly of the immune system, significantlyhigher or lower levels of IL17RLP gene expression may be detected incertain tissues (e.g., cancerous and wounded tissues) or bodily fluids(e.g., serum, plasma, urine, synovial fluid or spinal fluid) taken froman individual having such a disorder, relative to a “standard” IL17RLPgene expression level, i.e., the IL17RLP expression level in healthytissue from an individual not having the immune system disorder. Thus,the invention provides a diagnostic method useful during diagnosis ofsuch a disorder, which involves: (a) assaying IL17RLP gene expressionlevel in cells or body fluid of an individual; (b) comparing the IL17RLPgene expression level with a standard IL17RLP gene expression level,whereby an increase or decrease in the assayed IL17RLP gene expressionlevel compared to the standard expression level is indicative ofdisorder in the immune system.

[0025] An additional aspect of the invention is related to a method fortreating an individual in need of an increased level of IL17RLP activityin the body comprising administering to such an individual a compositioncomprising a therapeutically effective amount of an isolated IL17RLPpolypeptide of the invention or an agonist thereof.

[0026] A still further aspect of the invention is related to a methodfor treating an individual in need of a decreased level of IL17RLPactivity in the body comprising, administering to such an individual acomposition comprising a therapeutically effective amount of an IL17RLPantagonist. Preferred antagonists for use in the present invention areIL17RLP-specific antibodies.

BRIEF DESCRIPTION OF THE FIGURES

[0027]FIGS. 1A, 1B, and 1C show the nucleotide sequence (SEQ ID NO:1)and deduced amino acid sequence (SEQ ID NO:2) of IL17RLP.

[0028] The predicted leader sequence of about 19 amino acids isunderlined. Note that the methionine residue at the beginning of theleader sequence in FIGS. 1A, 1B, and 1C is shown in position number(positive) 1, whereas the leader positions in the corresponding sequenceof SEQ ID NO:2 are designated with negative position numbers. Thus, theleader sequence positions 1 to 19 in FIGS. 1A, 1B, and 1C correspond topositions −19 to −1 in SEQ ID NO:2.

[0029] Six potential asparagine-linked glycosylation sites are marked inthe amino acid sequence of IL17RLP. The sites are marked with the boldpound symbol (#) above the nucleotide sequence coupled with a bolded oneletter abbreviation for the asparagine (N) in the amino acid sequence inFIGS. 1A, 1B, and 1C; that is, the actual asparagine residues which arepotentially glycosylated is bolded in FIGS. 1A, 1B, and 1C. Thepotential N-linked glycosylation sequences are found at the followinglocations in the IL17RLP amino acid sequence: N-67 through W-70 (N-67,V-68, S-69, W-70); N-103 through E-106 (N-103, Y-104, T-105, E-106;N-156 through S-159 (N-156, F-157, T-158, S-159); N-183 through A-186(N-183, I-184, T-185, A-186); N-197 through T-200 (N-197, F-198, T-199,T-200); and N-283 through K-286 (N-283, K-284, S-285, K-286). Twopotential cAMP- and cGMP-dependent protein kinase phosphorylation sitesare also marked in FIGS. 1A, 1B, and 1C with a bolded lysine symbol (K)in the IL17RLP amino acid sequence and an asterisk (*) above the firstnucleotide encoding that lysine residue in the IL17RLP nucleotidesequence. The potential cAMP- and cGMP-dependent protein kinasephosphorylation sequences are found in the IL17RLP amino acid sequenceat the following locations: K-141 through threonine-231 (K-228, K-229,Q-230, T-231) and K-319 through S-322 (K-319, K-320, T-321, S-322).Three potential Protein Kinase C (PKC) phosphorylation sites are alsomarked in FIGS. 1A, 1B, and 1C with a bolded serine or tyrosine symbol(S or T) in the IL17RLP amino acid sequence and an asterisk (*) abovethe first nucleotide encoding that serine tyrosine residue in theIL17RLP nucleotide sequence. The potential PKC phosphorylation sequencesare found in the IL17RLP amino acid sequence at the following locations:S-77 through R-79 (S-77, I-78, R-79); T-89 through K-91 (T-89, G-90,K-91); and T-384 through K-386 (T-384, Q-385, K-386). Three potentialCasein Kinase II (CK2) phosphorylation sites are also marked in FIGS.1A, 1B, and 1C with a bolded serine symbol (S) in the IL17RLP amino acidsequence and an asterisk (*) above the first nucleotide encoding theappropriate serine residue in the IL17RLP nucleotide sequence. Thepotential CK2 phosphorylation sequences are found at the followinglocations in the IL17RLP amino acid sequence: S-178 through D-181(S-178, L-179, W-180, D-181); S-402 through D-405 (S-402, V-403, C-404,D-405); and S-414 through E-417 (S414, P-415, S-416, E-417). A singlepotential myristylation site is found in the IL17RLP amino acid sequenceshown in FIGS. 1A, 1B, and 1C. The potential myristylation site ismarked in FIGS. 1A, 1B, and 1C with a double underline delineating theamino acid residues representing the potential myristolation site in theIL17RLP amino acid sequence. The potential myristolation site is locatedat the following postion in the IL17RLP amino acid sequence: G-116through F-121 (G-116, G-117, K-118, W-119, T-120, F-121).

[0030] Mutations in one or more of the amino acid residues in theabove-recited potential structural features of the IL17RLP polypeptideare contemplated as mutations which may affect biological, structural,binding or other characteristics of an IL17RLP DNA or polypeptide of theinvention.

[0031]FIG. 2 shows the regions of identity between the amino acidsequences of the IL17RLP protein and translation product of the murinemRNA for IL-17 receptor (SEQ ID NO:3), determined by the computerprogram Bestfit (Wisconsin Sequence Analysis Package, Version 8 forUnix, Genetics Computer Group, University Research Park, 575 ScienceDrive, Madison, Wis. 53711) using the default parameters.

[0032]FIG. 3 shows an analysis of the IL17RLP amino acid sequence.Alpha, beta, turn and coil regions; hydrophilicity and hydrophobicity;amphipathic regions; flexible regions; antigenic index and surfaceprobability are shown. In the “Antigenic Index or Jameson-Wolf” graph,the positive peaks indicate locations of the highly antigenic regions ofthe IL17RLP protein, i.e., regions from which epitope-bearing peptidesof the invention can be obtained.

[0033] In the “Antigenic Index or Jameson-Wolf” graph, the positivepeaks indicate locations of the highly antigenic regions of the IL17RLPprotein, i.e., regions from which epitope-bearing peptides of theinvention can be obtained. Non-limiting examples of antigenicpolypeptides or peptides that can be used to generate IL17RLP-specificantibodies include: a polypeptide comprising amino acid residues fromabout a polypeptide comprising amino acid residues from about Ser-14 toabout Val-22 in SEQ ID NO:2, a polypeptide comprising amino acidresidues from about Cys-24 to about Pro-32 in SEQ ID NO:2, a polypeptidecomprising amino acid residues from about Ile-41 to about Arg-49 in SEQID NO:2, a polypeptide comprising amino acid residues from about Thr-89to about Val-97 in SEQ ID NO:2, a polypeptide comprising amino acidresidues from about Thr-110 to about Lys-118 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Ala-144 to aboutSer-152 in SEQ ID NO:2, a polypeptide comprising amino acid residuesfrom about Thr-240 to about Val-248 in SEQ ID NO:2, a polypeptidecomprising amino acid residues from about Gly-258 to about Thr-267 inSEQ ID NO:2, a polypeptide comprising amino acid residues from aboutLeu-280 to about Gly-288 in SEQ ID NO:2, a polypeptide comprising aminoacid residues from about Cys-404 to about Glu-412 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Pro-415 to aboutSer-423 in SEQ ID NO:2, a polypeptide comprising amino acid residuesfrom about Gly-409 to about Glu-417 in SEQ ID NO:2, and a polypeptidecomprising amino acid residues from about Cys-404 to about Leu-426 inFIGS. 1A, 1B, and 1C (which is identical to the sequence shown in SEQ IDNO:2 with exception to the numbering schemes as detailed above).

[0034] The data presented in FIG. 3 are also represented in tabular formin Table I. The data presented in Table I is identical to thatoriginally presented in FIG. 3. The columns are labeled with theheadings “Res”, “Position”, and Roman Numerals I-XIV. The columnheadings refer to the following features of the amino acid sequencepresented in FIG. 3 and Table I: “Res”: amino acid residue of SEQ IDNO:2 or FIGS. 1A, 1B, and 1C (which is the identical sequence shown inSEQ ID NO:2, with the exception that the residues are numbered 1-426 inFIGS. 1A, 1B, and 1C and −19 through 407 in SEQ ID NO:2); “Position”:position of the corresponding residue within SEQ ID NO:2 or FIGS. 1A,1B, and 1C (which is the identical sequence shown in SEQ ID NO:2, withthe exception that the residues are numbered 1-426 in FIGS. 1A, 1B, and1C and −19 through 406 in SEQ ID NO:2); I: Alpha,Regions—Garnier-Robson; II: Alpha, Regions—Chou-Fasman; III: Beta,Regions—Garnier-Robson; IV: Beta, Regions—Chou-Fasman; V: Turn,Regions—Garnier-Robson; VI: Turn, Regions—Chou-Fasman; VII: Coil,Regions—Garnier-Robson; VIII: Hydrophilicity Plot—Kyte-Doolittle; IX:Hydrophobicity Plot—Hopp-Woods; X: Alpha, Amphipathic Regions—Eisenberg;XI: Beta, Amphipathic Regions—Eisenberg; XII: FlexibleRegions—Karplus-Schulz; XIII: Antigenic Index—Jameson-Wolf; and XIV:Surface Probability Plot—Emini.

DETAILED DESCRIPTION

[0035] The present invention provides isolated nucleic acid moleculescomprising a polynucleotide encoding a IL17RLP polypeptide having theamino acid sequence shown in SEQ ID NO:2, which was determined bysequencing a cloned cDNA. The nucleotide sequence shown in FIGS. 1A, 1B,and 1C (SEQ ID NO:1) was obtained by sequencing the HAPOR40 clone, whichwas deposited on Aug. 8, 1997 at the American Type Culture Collection,10801 University Boulevard, Manassas, Va. 20110-2209, and givenaccession number ATCC 209198. The deposited clone is contained in thepBluescript SK(−) plasmid (Stratagene, La Jolla, Calif.).

[0036] The IL17RLP protein of the present invention shares sequencehomology with the translation product of the murine MRNA for IL-17receptor (FIG. 2; SEQ ID NO:3). Murine IL-17 receptor is thought to bean important component of the IL-17 cytokine signal transductionpathway. IL-17 receptor appears to be structurally unrelated to anymembers of previously described cytokine receptor families. TheIL-17/IL-17 receptor complex activates NF-κB activity. NF-κB is atranscription factor known to regulate a large number of gene productsinvolved in growth control. NF-κB-induced gene products includemolecules involved in immune, inflammatory, or actute phase responses,such as immunoglobulin light chain, major histocompatibility complex(MHC), IL-2R α chain, and cytokines such as IL-1β, IL-6, and TNFα. NF-κBdirectly stimulates the HIV enhancer in T-cells and can itself beactivated by different viral proteins with oncogenic potential, such asthe hepatitis B virus HBX protein, EBV LMP1, and HTLV-1 Tax protein. Theinduction of NF-κB by Tax results in up-regulation of IL-2 and IL-2R andsubsequently uncontrolled T-cell growth. IL-17 and HVS13, a gene productof HVS and a murine counterpart of IL-17, strongly induce IL-6expression. IL-6 is a potent growth factor for myelomas, plasmacytomas,and hybridomas and is involved in the growth of Lennert's LymphomaT-cells.

Nucleic Acid Molecules

[0037] Unless otherwise indicated, all nucleotide sequences determinedby sequencing a DNA molecule herein were determined using an automatedDNA sequencer (such as the Model 373 from Applied Biosystems, Inc.,Foster City, Calif.), and all amino acid sequences of polypeptidesencoded by DNA molecules determined herein were predicted by translationof a DNA sequence determined as above. Therefore, as is known in the artfor any DNA sequence determined by this automated approach, anynucleotide sequence determined herein may contain some errors.Nucleotide sequences determined by automation are typically at leastabout 90% identical, more typically at least about 95% to at least about99.9% identical to the actual nucleotide sequence of the sequenced DNAmolecule. The actual sequence can be more precisely determined by otherapproaches including manual DNA sequencing methods well known in theart. As is also known in the art, a single insertion or deletion in adetermined nucleotide sequence compared to the actual sequence willcause a frame shift in translation of the nucleotide sequence such thatthe predicted amino acid sequence encoded by a determined nucleotidesequence will be completely different from the amino acid sequenceactually encoded by the sequenced DNA molecule, beginning at the pointof such an insertion or deletion.

[0038] By “nucleotide sequence” of a nucleic acid molecule orpolynucleotide is intended, for a DNA molecule or polynucleotide, asequence of deoxyribonucleotides, and for an RNA molecule orpolynucleotide, the corresponding sequence of ribonucleotides (A, G, Cand U), where each thymidine deoxyribonucleotide (T) in the specifieddeoxyribonucleotide sequence is replaced by the ribonucleotide uridine(U).

[0039] Using the information provided herein, such as the nucleotidesequence in FIGS. 1A, 1B, and 1C (SEQ ID NO:1), a nucleic acid moleculeof the present invention encoding a IL17RLP polypeptide may be obtainedusing standard cloning and screening procedures, such as those forcloning cDNAs using mRNA as starting material. Illustrative of theinvention, the nucleic acid molecule described in FIGS. 1A, 1B, and 1C(SEQ ID NO:1) was discovered in a cDNA library derived from human adultpulmonary tissue.

[0040] Additional clones of the same gene were also identified in cDNAlibraries from the following tissues: Crohn's Disease tissue, kidneypyramid, cortex, and medulla tissues, hippocampus, frontal cortex of thebrain from a patient with epilepsy, adrenal gland tumor, striatumdepression, osteclastoma, endometrial tumor, and hypothalamus from apatient with Schizophrenia.

[0041] The determined nucleotide sequence of the IL17RLP cDNA of FIGS.1A, 1B, and 1C (SEQ ID NO:1) contains an open reading frame encoding aprotein of 426 amino acid residues, with an initiation codon atnucleotide positions 10-12 of the nucleotide sequence in FIGS. 1A, 1B,and 1C (SEQ ID NO:1), and a deduced molecular weight of about 47.1 kDa.The amino acid sequence of the IL17RLP protein shown in SEQ ID NO:2 isabout 28.6% identical to the murine mRNA for IL-17 receptor (FIG. 2;Yao, Z., et al., Immunity 3:811-821 (1995); GenBank Accession No.U31993).

[0042] The open reading frame of the IL17RLP gene shares sequencehomology with the translation product of the murine mRNA for IL-17receptor (FIG. 2; SEQ ID NO:3). The murine IL-17 receptor is thought tobe important in regulation of immune cell signal transduction cascadesand the resulting regulation of cell growth, differentiation, andactivation-state. The homology between the murine IL-17 receptor andIL17RLP indicates that IL17RLP may also be involved in regulation ofimmune cell signal transduction cascades and the resulting regulation ofcell growth, differentiation, and activation-state.

[0043] As one of ordinary skill would appreciate, due to thepossibilities of sequencing errors discussed above, the actual completeIL17RLP polypeptide encoded by the deposited cDNA, which comprises about426 amino acids, may be somewhat longer or shorter. More generally, theactual open reading frame may be anywhere in the range of ±20 aminoacids, more likely in the range of ±10 amino acids, of that predictedfrom either the first methionine codon from the N-terminus shown inFIGS. 1A, 1B, and 1C (SEQ ID NO:1). It will further be appreciated that,depending on the analytical criteria used for identifying variousfunctional domains, the exact “address” of the extracellular,intracellular and transmembrane domains of the IL17RLP polypeptide maydiffer slightly from the predicted positions above. For example, theexact location of the IL17RLP extracellular domain in SEQ ID NO:2 mayvary slightly (e.g., the address may “shift” by about 1 to about 20residues, more likely about 1 to about 5 residues) depending on thecriteria used to define the domain. In this case, the ends of thetransmembrane domain and the beginning of the extracellular domain werepredicted on the basis of the identification of the hydrophobic aminoacid sequence in the above indicated positions, as shown in FIG. 3. Inany event, as discussed further below, the invention further providespolypeptides having various residues deleted from the N-terminus of thecomplete polypeptide, including polypeptides lacking one or more aminoacids from the N-terminus of the extracellular domain described herein,which constitute soluble forms of the extracellular domain of theIL17RLP protein.

[0044] It will further be appreciated that, depending on the analyticalcriteria used for identifying the exact location of the cleavage site ofthe precursor form of the mature IL17RLP molecule shown in SEQ ID NO:2may vary slightly, depending on the criteria used to define the cleavagesite. In this case, the ends of the signal peptide and the beginning ofthe mature IL17RLP molecule were predicted using the HGSI SignalPcomputer algorithm. One of skill in the art will realize that anotherwidely accepted computer algorithm used to predict potential sites ofpolypeptide cleavage, PSORT, will predict the cleavage of an N-terminalsignal peptide from the IL17RLP polypeptide at a point slightlydifferent from that predicted by the HGSI SignalP algorithm. In eithercase, as discussed further below, the invention further providespolypeptides having various residues deleted from the N-terminus of thecomplete polypeptide, including polypeptides corresponding to either ofthe predicted mature IL17RLP polypeptides described herein.

[0045] Leader and Mature Sequences

[0046] The amino acid sequence of the complete IL17RLP protein includesa leader sequence and a mature protein, as shown in SEQ ID NO:2. More inparticular, the present invention provides nucleic acid moleculesencoding a mature form of the IL17RLP protein. Thus, according to thesignal hypothesis, once export of the growing protein chain across therough endoplasmic reticulum has been initiated, proteins secreted bymammalian cells have a signal or secretory leader sequence which iscleaved from the complete polypeptide to produce a secreted “mature”form of the protein. Most mammalian cells and even insect cells cleavesecreted proteins with the same specificity. However, in some cases,cleavage of a secreted protein is not entirely uniform, which results intwo or more mature species of the protein. Further, it has long beenknown that the cleavage specificity of a secreted protein is ultimatelydetermined by the primary structure of the complete protein, that is, itis inherent in the amino acid sequence of the polypeptide. Therefore,the present invention provides a nucleotide sequence encoding the matureIL17RLP polypeptide having the amino acid sequence encoded by the cDNAclone identified as ATCC Deposit No. 209198. By the “mature IL17RLPpolypeptide having the amino acid sequence encoded by the cDNA clone inATCC Deposit No. 209198” is meant the mature form(s) of the IL17RLPprotein produced by expression in a mammalian cell (e.g., COS cells, asdescribed below) of the complete open reading frame encoded by the humanDNA sequence of the clone contained in the deposited clone HAPOR40.

[0047] In addition, methods for predicting whether a protein has asecretory leader as well as the cleavage point for that leader sequenceare available. For instance, the method of McGeoch (Virus Res. 3:271-286(1985)) uses the information from a short N-terminal charged region anda subsequent uncharged region of the complete (uncleaved) protein. Themethod of von Heinje (Nucleic Acids Res. 14:4683-4690 (1986)) uses theinformation from the residues surrounding the cleavage site, typicallyresidues −13 to +2 where +1 indicates the amino terminus of the matureprotein. The accuracy of predicting the cleavage points of knownmammalian secretory proteins for each of these methods is in the rangeof 75-80% (von Heinje, supra). However, the two methods do not alwaysproduce the same predicted cleavage point(s) for a given protein.

[0048] In the present case, the deduced amino acid sequence of thecomplete IL17RLP polypeptide was analyzed by a variation of the computerprogram “PSORT”, available from Dr. Kenta Nakai of the Institute forChemical Research, Kyoto University (Nakai, K. and Kanehisa, M. Genomics14:897-911 (1992)), which is an expert system for predicting thecellular location of a protein based on the amino acid sequence. As partof this computational prediction of localization, the methods of McGeochand von Heinje are incorporated. Thus, the computation analysis abovepredicted a single cleavage site within the complete amino acid sequenceshown in SEQ ID NO:2 (see above discussion).

[0049] As one of ordinary skill would appreciate from the abovediscussions, due to the possibilities of sequencing errors as well asthe variability of cleavage sites in different known proteins, themature IL17RLP polypeptide encoded by the deposited cDNA is expected toconsist of about 407 amino acids (presumably residues 1 to 407 of SEQ IDNO:2, but may consist of any number of amino acids in the range of about407-412 amino acids; and the actual leader sequence(s) of this proteinis expected to be 14-19 amino acids (presumably residues −19 through −1of SEQ ID NO:2), but may consist of any number of amino acids in therange of 14-19 amino acids.

[0050] As indicated, nucleic acid molecules of the present invention maybe in the form of RNA, such as mRNA, or in the form of DNA, including,for instance, cDNA and genomic DNA obtained by cloning or producedsynthetically. The DNA may be double-stranded or single-stranded.Single-stranded DNA or RNA may be the coding strand, also known as thesense strand, or it may be the non-coding strand, also referred to asthe anti-sense strand.

[0051] By “isolated” nucleic acid molecule(s) is intended a nucleic acidmolecule, DNA or RNA, which has been removed from its native environmentFor example, recombinant DNA molecules contained in a vector areconsidered isolated for the purposes of the present invention. Furtherexamples of isolated DNA molecules include recombinant DNA moleculesmaintained in heterologous host cells or purified (partially orsubstantially) DNA molecules in solution. Isolated RNA molecules includein vivo or in vitro RNA transcripts of the DNA molecules of the presentinvention. Isolated nucleic acid molecules according to the presentinvention further include such molecules produced synthetically.

[0052] Isolated nucleic acid molecules of the present invention includeDNA molecules comprising an open reading frame (ORF) with an initiationcodon at positions 10-12 of the nucleotide sequence shown in FIGS. 1A,1B, and 1C (SEQ ID NO:1).

[0053] Also included are DNA molecules comprising the coding sequencefor the predicted mature IL17RLP protein shown at positions 1-407 of SEQID NO:2.

[0054] In addition, isolated nucleic acid molecules of the inventioninclude DNA molecules which comprise a sequence substantially differentfrom those described above but which, due to the degeneracy of thegenetic code, still encode the IL17RLP protein. Of course, the geneticcode and species-specific codon preferences are well known in the art.Thus, it would be routine for one skilled in the art to generate thedegenerate variants described above, for instance, to optimize codonexpression for a particular host (e.g., change codons in the human mRNAto those preferred by a bacterial host such as E. coli).

[0055] In another aspect, the invention provides isolated nucleic acidmolecules encoding the IL17RLP polypeptide having an amino acid sequenceencoded by the cDNA clone contained in the plasmid deposited as ATCCDeposit No. 209198 on Aug. 8, 1997.

[0056] Preferably, this nucleic acid molecule will encode the maturepolypeptide encoded by the above-described deposited cDNA clone.

[0057] The invention further provides an isolated nucleic acid moleculehaving the nucleotide sequence shown in FIGS. 1A, 1B, and 1C (SEQ IDNO:1) or the nucleotide sequence of the IL17RLP cDNA contained in theabove-described deposited clone, or a nucleic acid molecule having asequence complementary to one of the above sequences. Such isolatedmolecules, particularly DNA molecules, are useful as probes for genemapping, by in situ hybridization with chromosomes, and for detectingexpression of the IL17RLP gene in human tissue, for instance, byNorthern blot analysis.

[0058] The present invention is further directed to nucleic acidmolecules encoding portions of the nucleotide sequences described hereinas well as to fragments of the isolated nucleic acid molecules describedherein. In particular, the invention provides a polynucleotide having anucleotide sequence representing the portion of SEQ ID NO:1 whichconsists of positions 1-1290 of SEQ ID NO:1.

[0059] In addition, the invention provides nucleic acid molecules havingnucleotide sequences related to extensive portions of SEQ ID NO:1 whichhave been determined from the following related cDNA clones: HHPCH63R(SEQ ID NO:4) and HETCC45RA (SEQ ID NO:5). Such polynucleotides maypreferably be excluded from the invention.

[0060] Further, the invention includes a polynucleotide comprising anyportion of at least about 30 nucleotides, preferably at least about 50nucleotides, of SEQ ID NO:1 from residue 50-1800, 100-1800, 200-1800,300-1800, 400-1800, 500-1800, 600-1800, 50-650, 100-650, 200-650,300-650, 400-650, 500-650, 50-500, 100-500, 200-500, 300-500, 400-500,50-400, 100-400, 200-400, 300-400, 50-300, 100-300, 200-300, 50-200,100-200, and 50-100.

[0061] More generally, by a fragment of an isolated nucleic acidmolecule having the nucleotide sequence of the deposited cDNA or thenucleotide sequence shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) isintended fragments at least about 15 nt, and more preferably at leastabout 20 nt, still more preferably at least about 30 nt, and even morepreferably, at least about 40 nt in length which are useful asdiagnostic probes and primers as discussed herein. Of course, largerfragments 50-300 nt in length are also useful according to the presentinvention as are fragments corresponding to most, if not all, of thenucleotide sequence of the deposited cDNA or as shown in FIGS. 1A, 1B,and 1C (SEQ ID NO:1). By a fragment at least 20 nt in length, forexample, is intended fragments which include 20 or more contiguous basesfrom the nucleotide sequence of the deposited cDNA or the nucleotidesequence as shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1). Preferrednucleic acid fragments of the present invention include nucleic acidmolecules encoding epitope-bearing portions of the IL17RLP polypeptideas identified in FIG. 3 and described in more detail below.

[0062] In specific embodiments, the polynucleotide fragments of theinvention encode a polypeptide which demonstrates a functional activity.By a polypeptide demonstrating “functional activity” is meant, apolypeptide capable of displaying one or more known functionalactivities associated with a complete, mature or active form of theIL17RLP polypeptide. Such functional activities include, but are notlimited to, biological activity ((e.g., activation of signaltransduction pathways resulting in the stimulation of the NF-κBtranscription factor family, the secretion of IL-6, and thecostimulation of T-cell proliferation; induction of IL-6, IL-8, G-CSF,Prostaglandin E (PGE₂), and intracellular adhesion molecule (ICAM)-1expression; regulation of hematopoietic stem and progenitor cell growthand expansion; myelosuppressive activity for stem and immature subsetsof myeloid progenitors; activation and stimulation of hematopoiesis ingeneral (more specifically, neutrophil hematopoiesis); enhancement oferythropoiesis; suppression of lymphopoiesis and myelopoiesis; andstrong suppression of monocytopoiesis)), antigenicity [ability to bind(or compete with a IL17RLP polypeptide for binding) to an anti-IL17RLPantibody], immunogenicity (ability to generate antibody which binds toan IL17RLP polypeptide), the ability to form polymers with other IL17RLPor IL17RLP-like polypeptides, and ability to bind to a receptor orligand for an IL17RLP polypeptide.

[0063] Preferred nucleic acid fragments of the present invention alsoinclude nucleic acid molecules encoding one or more of the followingdomains of IL17RLP: Domain I (i.e., Val-49 through Leu-62 of SEQ ID NO:2(Val-68 through Leu-81 of FIGS. 1A, 1B, and 1C)); Domain II (Cys-154through Thr-166 of SEQ ID NO:2 (i.e., Cys-173 through Thr-185 of FIGS.1A, 1B, and 1C)); Domain III (Gln-202 through Gln-208 of SEQ ID NO:2(i.e., Gln-221 through Gln-227 of FIGS. 1A, 1B, and 1C)); Domain IV(Asp-241 through Val-249 of SEQ ID NO:2 (i.e., Asp-260 through Val-268of FIGS. 1A, 1B, and 1C)); Domain V (Thr-255 through Leu-261 of SEQ IDNO:2 (i.e., Thr-274 through Leu-280 of FIGS. 1A, 1B, and 1C)); Domain VI(Leu-310 through Tyr-319 of SEQ ID NO:2 (i.e., Leu-329 through Tyr-338of FIGS. 1A, 1B, and 1C)); Domain VII (Cys-340 through Leu-346 of SEQ IDNO:2 (i.e., Cys-359 through Leu-365 of FIGS. 1A, 1B, and 1C)); andDomain VIII (Ile-354 through Gly-358 of SEQ ID NO:2 (i.e., Ile-373through Gly-377 of FIGS. 1A, 1B, and 1C)).

[0064] In specific embodiments, the polynucleotide fragments of theinvention encode antigenic regions. Non-limiting examples of antigenicpolypeptides or peptides that can be used to generate IL17RLP-specificantibodies include: a polypeptide comprising amino acid residues fromabout from about Ser-14 to about Val-22, from about Cys-24 to aboutPro-32, from about Ile-41 to about Arg-49, from about Thr-89 to about,from about Thr-110 to about Lys-118, from about Ala-144 to aboutSer-152, from about Thr-240 to about Val-248, from about Gly-258 toabout Thr-267, from about Leu-280 to about Gly-288, from about Cys-404to about Glu-412, from about Pro-415 to about Ser-423, from aboutGly-409 to about Glu-417, and from about Cys404 to about Leu-426 inFIGS. 1A, 1B, and 1C (which is the identical sequence to that shown inSEQ ID NO:2, with the exception of the numbering schemes as describedabove).

[0065] In additional embodiments, the polynucleotides of the inventionencode functional attributes of IL17RLP. Preferred embodiments of theinvention in this regard include fragments that comprise alpha-helix andalpha-helix forming regions (“alpha-regions”), beta-sheet and beta-sheetforming regions (“beta-regions”), turn and turn-forming regions(“turn-regions”), coil and coil-forming regions (“coil-regions”),hydrophilic regions, hydrophobic regions, alpha amphipathic regions,beta amphipathic regions, flexible regions, surface-forming regions andhigh antigenic index regions of IL17RLP.

[0066] The data representing the structural or functional attributes ofIL17RLP set forth in FIG. 3 and/or Table I, as described above, wasgenerated using the various modules and algorithms of the DNA*STAR seton default parameters. In a preferred embodiment, the data presented incolumns VIII, IX, XIII, and XIV of Table I can be used to determineregions of IL17RLP which exhibit a high degree of potential forantigenicity. Regions of high antigenicity are determined from the datapresented in columns VIII, IX, XIII, and/or IV by choosing values whichrepresent regions of the polypeptide which are likely to be exposed onthe surface of the polypeptide in an environment in which antigenrecognition may occur in the process of initiation of an immuneresponse.

[0067] Certain preferred regions in these regards are set out in FIG. 3,but may, as shown in Table I, be represented or identified by usingtabular representations of the data presented in FIG. 3. The DNA*STARcomputer algorithm used to generate FIG. 3 (set on the original defaultparameters) was used to present the data in FIG. 3 in a tabular format(See Table I). The tabular format of the data in FIG. 3 may be used toeasily determine specific boundaries of a preferred region.

[0068] The above-mentioned preferred regions set out in FIG. 3 and inTable I include, but are not limited to, regions of the aforementionedtypes identified by analysis of the amino acid sequence set out in FIGS.1A, 1B, and 1C. As set out in FIG. 3 and in Table I, such preferredregions include Garnier-Robson alpha-regions, beta-regions,turn-regions, and coil-regions, Chou-Fasman alpha-regions, beta-regions,and coil-regions, Kyte-Doolittle hydrophilic regions and hydrophobicregions, Eisenberg alpha- and beta-amphipathic regions, Karplus-Schulzflexible regions, Emini surface-forming regions and Jameson-Wolf regionsof high antigenic index. TABLE I Res Position I II III IV V VI VII VIIIIX X XI XII XIII XIV Met 1 A A . . . . . −1.43 0.61 . . . −0.60 0.30 Ser2 A A . . . . . −1.86 0.87 . . . −0.60 0.20 Leu 3 A A . . . . . −1.771.13 . . . −0.60 0.13 Val 4 A A . . . . . −2.19 1.09 . . . −0.60 0.17Leu 5 A A . . . . . −2.39 1.16 . . . −0.60 0.11 Leu 6 A A . . . . .−2.38 1.27 . . . −0.60 0.13 Ser 7 A A . . . . . −2.89 1.09 . . . −0.600.18 Leu 8 A A . . . . . −2.74 1.13 * * . −0.60 0.18 Ala 9 A A . . . . .−1.78 1.01 * * . −0.60 0.11 Ala 10 A A . . . . . −1.27 0.33 * . . −0.300.17 Leu 11 A A . . . . . −1.04 0.33 * * . −0.30 0.27 Cys 12 A . B . . T. −1.60 0.14 * . . 0.10 0.27 Arg 13 . . B . . T . −1.00 0.29 * . . 0.400.20 Ser 14 . . B . . T . −0.30 0.21 . . . 0.70 0.37 Ala 15 . . B . . T. 0.29 −0.47 . . . 1.75 1.37 Val 16 . . . . . . C 0.89 −1.04 * . F 2.501.21 Pro 17 . . . . T . . 1.24 −0.61 * . F 3.00 1.39 Arg 18 . . . . T .. 0.28 −0.51 . . F 2.70 1.99 Glu 19 . . B . . . . 0.58 −0.37 . . F 1.701.99 Pro 20 . . B . . . . 0.50 −0.61 . . F 1.70 2.23 Thr 21 . . B . . .. 1.01 −0.47 . . F 0.95 0.61 Val 22 . . B . . . . 0.92 −0.04 . . . 0.500.35 Gln 23 . . B . . . . 0.81 0.34 . . . 0.18 0.30 Cys 24 . . B . . T .0.50 −0.09 * . F 1.41 0.36 Gly 25 . . B . . T . 0.37 −0.09 * . F 1.690.71 Ser 26 . . . . T T . 0.47 −0.30 * . F 2.37 0.40 Glu 27 . . . . T T. 1.02 −0.27 * . F 2.80 1.16 Thr 28 . . . . . . C 0.81 −0.46 * . F 2.121.57 Gly 29 . . . . . . C 1.48 −0.46 . . F 1.84 1.82 Pro 30 . . . . . .C 1.53 −0.84 . . F 1.86 1.82 Ser 31 . . . . . T C 1.23 0.07 . . F 0.881.32 Pro 32 . . . . . T C 0.42 0.20 . * F 0.60 1.32 Glu 33 A . . . . T .0.73 0.46 . . F −0.05 0.71 Trp 34 A . . . . T . 1.04 0.43 . * . −0.200.91 Met 35 A A . . . . . 1.26 0.54 . * . −0.60 0.80 Leu 36 A A . . . .. 0.74 0.11 . * . −0.30 0.77 Gln 37 A A . . . . . 0.07 0.80 . * . −0.600.61 His 38 . A B . . . . −0.14 0.57 . * . −0.60 0.43 Asp 39 . A . . T .. −0.20 0.39 . . . 0.10 0.81 Leu 40 . A . . . . C 0.40 0.13 . . . 0.240.46 Ile 41 . . B . . T . 0.40 −0.27 * * . 1.38 0.57 Pro 42 . . B . . T. 0.51 −0.09 * * F 1.87 0.28 Gly 43 . . . . T T . 0.54 −0.09 * * F 2.610.66 Asp 44 . . . . T T . −0.27 −0.77 * . F 3.40 1.58 Leu 45 . A B . . .. 0.66 −0.77 * * F 2.11 0.84 Arg 46 . A B . . . . 0.69 −1.20 * * F 1.921.67 Asp 47 . A B . . . . 0.90 −0.99 . * F 1.43 0.74 Leu 48 . A B . . .. 1.03 −0.99 . . . 1.09 1.56 Arg 49 . A B . . . . 0.18 −1.24 . . . 0.751.23 Val 50 . A B B . . . 0.68 −0.60 * . . 0.60 0.55 Glu 51 . A B B . .. 0.26 −0.11 * * F 0.45 0.96 Pro 52 . A B B . . . −0.04 −0.31 . * F 0.450.70 Val 53 . . B B . . . −0.09 0.07 * * F 0.00 1.27 Thr 54 . . B B . .. −0.79 0.07 * * F −0.15 0.55 Thr 55 . . B B . . . −0.24 0.57 * . F−0.45 0.36 Ser 56 . . B B . . . −0.59 0.63 * . F −0.45 0.69 Val 57 . . BB . . . −0.38 0.41 . . F −0.45 0.47 Ala 58 . . B B . . . 0.23 −0.07 . .F 0.45 0.55 Thr 59 . . B . . T . 0.24 0.20 . * F 0.25 0.64 Gly 60 . . B. . T . −0.33 0.20 . . F 0.40 1.16 Asp 61 . . B . . T . −0.84 0.24 . . F0.25 0.80 Tyr 62 . . B . . T . −0.59 0.43 . * . −0.20 0.46 Ser 63 . . BB . . . −0.00 0.56 . * . −0.60 0.46 Ile 64 . . B B . . . −0.54 0.53 . *. −0.60 0.44 Leu 65 . . B B . . . −0.50 1.17 . * . −0.60 0.21 Met 66 . .B B . . . −0.79 0.80 . * . −0.60 0.21 Asn 67 . . B B . . . −1.401.33 * * . −0.60 0.31 Val 68 . . B B . . . −1.91 1.29 * * . −0.60 0.28Ser 69 . . B B . . . −0.91 1.29 * * . −0.60 0.24 Trp 70 . . B B . . .−0.69 0.67 * * . −0.60 0.29 Val 71 . . B B . . . −0.09 0.77 . * . −0.600.39 Leu 72 A . . B . . . −0.68 0.13 * * . −0.30 0.49 Arg 73 A . . B . .. −0.12 0.24 * * . −0.30 0.47 Ala 74 A . . B . . . −0.71 −0.29 * * .0.30 0.85 Asp 75 A . . B . . . −0.31 −0.24 * * . 0.30 0.72 Ala 76 A . .B . . . −0.27 −0.93 * * . 0.60 0.72 Ser 77 A . . B . . . −0.27 −0.24 * *. 0.30 0.59 Ile 78 A . . B . . . −0.33 −0.06 * * . 0.30 0.29 Arg 79 A .. B . . . −0.33 −0.06 * * . 0.30 0.57 Leu 80 A . . B . . . −0.64−0.06 * * . 0.30 0.43 Leu 81 A . . B . . . −0.01 0.04 * * . −0.30 0.89Lys 82 A . . B . . . −0.60 −0.64 * * F 0.75 0.91 Ala 83 A . . B . . .−0.38 0.04 * * F −0.15 0.77 Thr 84 A . . B . . . −1.34 −0.07 * . F 0.450.50 Lys 85 . . B B . . . −0.84 −0.11 * . F 0.45 0.19 Ile 86 . . B B . .. −0.38 0.37 . * . −0.30 0.27 Cys 87 . . B B . . . −0.38 0.30 * * .−0.30 0.18 Val 88 . . B B . . . −0.09 −0.19 * * . 0.58 0.18 Thr 89 . . BB . . . 0.22 0.20 * * F 0.41 0.35 Gly 90 . . . . T T . −0.52 −0.09 * * F2.24 1.05 Lys 91 . . . . T T . 0.37 0.13 * * F 1.92 1.22 Ser 92 . . . .T T . 0.73 −0.11 . * F 2.80 1.47 Asn 93 . . . . T T . 1.34 −0.21 . * F2.52 1.99 Phe 94 . . . . T . . 1.36 0.11 . * F 1.44 1.56 Gln 95 . . . .T . . 1.03 0.50 * * F 0.86 1.56 Ser 96 . . . . T T . 0.13 0.69 * * .0.48 0.52 Tyr 97 . . B . . T . 0.54 0.93 . * . −0.20 0.44 Ser 98 . . . .T T . −0.12 0.14 . * . 0.50 0.50 Cys 99 . . B . . T . 0.58 0.31 . * .0.10 0.20 Val 100 . . B . . . . 0.33 0.33 . * . 0.12 0.21 Arg 101 . . B. . . . 0.32 0.33 . * . 0.34 0.24 Cys 102 . . B . . T . 0.57 0.43 * * .0.46 0.65 Asn 103 . . . . T T . 0.28 −0.14 * * . 2.13 1.52 Tyr 104 . . .. T T . 0.24 −0.29 * * . 2.20 0.78 Thr 105 . . . . . T C 1.10 0.50 * * .1.03 1.26 Glu 106 . A B B . . . 0.68 0.33 . * . 0.51 1.36 Ala 107 . A BB . . . 1.34 0.41 . . . −0.01 1.25 Phe 108 . A B B . . . 1.03 0.06 * * F0.22 1.50 Gln 109 . A B B . . . 1.39 0.06 * * F 0.00 1.25 Thr 110 . A BB . . . 1.49 0.06 * * F 0.00 2.43 Gln 111 . . B B . . . 1.19 −0.01 * * F0.94 4.34 Thr 112 . . . B . . C 1.43 −0.41 * * F 1.48 3.36 Arg 113 . . .B . . C 1.79 −0.39 . * F 1.82 2.30 Pro 114 . . . . T T . 1.83 −0.44 . *F 2.76 1.32 Ser 115 . . . . T T . 1.86 −0.84 . * F 3.40 1.82 Gly 116 . .. . T T . 1.54 −0.41 . * F 2.61 0.98 Gly 117 . . . . T T . 1.16 0.07 . *F 1.67 0.91 Lys 118 . . . B T . . 0.74 0.43 . * F 0.63 0.59 Trp 119 . .B B . . . 0.71 0.43 * . . −0.26 0.80 Thr 120 . . B B . . . 0.12 0.76 * *. −0.45 1.26 Phe 121 . . B B . . . 0.12 1.01 . * . −0.60 0.44 Ser 122 .. B B . . . −0.23 1.44 . * . −0.60 0.42 Tyr 123 . . B B . . . −0.49 1.31. * . −0.60 0.25 Ile 124 . . . B T . . −1.06 1.26 . * . −0.20 0.45 Gly125 . . . B . . C −0.74 1.11 . * . −0.40 0.25 Phe 126 . . . B . . C−0.86 0.73 . * . −0.40 0.27 Pro 127 . . B . . . . −0.56 0.66 . * . −0.400.32 Val 128 . . B . . . . −0.62 0.37 . * . −0.10 0.52 Glu 129 . . B . .. . −0.59 0.43 . * . −0.40 0.87 Leu 130 . . B B . . . −0.49 0.29 . * .−0.30 0.42 Asn 131 . . B B . . . −0.49 0.61 . * . −0.60 0.88 Thr 132 . .B B . . . −1.17 0.76 . . . −0.60 0.44 Val 133 . . B B . . . −0.66 1.44 .. . −0.60 0.38 Tyr 134 . . B B . . . −1.24 1.19 . . . −0.60 0.23 Phe 135. . B B . . . −0.47 1.29 . . . −0.60 0.16 Ile 136 . . B B . . . −0.471.30 . . . −0.60 0.30 Gly 137 . . B . . . . −1.04 1.06 . . . −0.40 0.30Ala 138 . . B . . . . −0.40 0.99 . . . −0.40 0.25 His 139 . . . . . . C−0.16 0.63 * . . −0.20 0.54 Asn 140 . . . . . . C −0.04 0.34 . . . 0.100.88 Ile 141 . . . . . T C 0.84 0.41 . . . 0.00 0.88 Pro 142 . . . . . TC 0.59 0.31 * . F 0.60 1.04 Asn 143 . . . . T T . 1.18 0.43 * . F 0.350.64 Ala 144 . . . . . T C 1.21 0.43 . . F 0.64 1.47 Asn 145 . . . . . .C 1.21 −0.26 . * . 1.53 1.65 Met 146 . . B . . . . 1.76 −0.69 . * . 1.971.71 Asn 147 . . . . . T C 1.76 −0.66 . * F 2.86 1.68 Glu 148 . . . . TT . 1.46 −0.73 . * F 3.40 1.61 Asp 149 . . . . T T . 1.44 −0.74 . . F3.06 2.19 Gly 150 . . . . . T C 1.14 −0.74 . . F 2.52 1.35 Pro 151 . . .. . . C 0.89 −0.76 . . F 1.98 1.04 Ser 152 . . . B . . C 0.89 −0.11 . *F 0.99 0.46 Met 153 . . B B . . . 0.19 0.29 * * . −0.30 0.75 Ser 154 . .B B . . . −0.12 0.64 . * . −0.60 0.42 Val 155 . . B B . . . −0.08 0.70. * . −0.60 0.45 Asn 156 . . B B . . . −0.08 0.70 . * . −0.60 0.61 Phe157 . . B B . . . −0.12 0.51 . * . −0.60 0.71 Thr 158 . . . B T . .−0.19 0.56 . * F −0.05 0.94 Ser 159 . . . . . T C −0.70 0.49 . * F 0.150.31 Pro 160 . . . . T T . 0.16 0.77 . * F 0.35 0.30 Gly 161 . . . . T T. 0.12 −0.01 . . F 1.25 0.35 Cys 162 A . . . . T . −0.07 −0.00 . . .0.70 0.35 Leu 163 A A . . . . . −0.36 0.30 * . . −0.30 0.16 Asp 164 A A. . . . . −0.01 0.49 * . . −0.60 0.16 His 165 A A . . . . . −0.040.06 * * . −0.30 0.60 Ile 166 A A . . . . . 0.34 0.24 * . . −0.15 1.13Met 167 A A . . . . . 1.06 −0.44 * * . 0.45 1.36 Lys 168 A A . . . . .1.91 −0.44 * * . 0.45 1.99 Tyr 169 A A . . . . . 1.24 −0.94 * . F 0.905.69 Lys 170 A A . . . . . 0.42 −1.06 * . F 0.90 3.08 Lys 171 A A . . .. . 1.36 −1.03 * . F 0.90 1.14 Lys 172 A A . . . . . 1.37 −1.03 * * F0.90 1.46 Cys 173 . A B . . . . 0.98 −1.29 * . . 0.60 0.74 Val 174 . A B. . . . 0.92 −0.86 * . . 0.60 0.36 Lys 175 . A B . . . . 0.07 −0.47 * .F 0.45 0.24 Ala 176 . A B . . . . −0.27 0.21 * . F 0.01 0.38 Gly 177 . .B . . T . −0.31 0.56 * . F 0.27 0.53 Ser 178 . . . . . T C 0.14 −0.09. * F 1.53 0.44 Leu 179 . . . . T T . 1.00 0.34 * * F 1.29 0.68 Trp 180. . . . T T . 0.07 0.24 * * F 1.60 1.11 Asp 181 . . . . . T C 0.34 0.50. * F 0.79 0.58 Pro 182 . . . . T T . 0.10 0.60 . * F 0.98 1.01 Asn 183. . . . T T . −0.27 0.41 * . F 0.67 0.97 Ile 184 A . . . . T . 0.590.07 * * . 0.26 0.31 Thr 185 A . . . . . . 0.92 0.07 * * . −0.10 0.40Ala 186 A . . . . . . 0.92 −0.36 . * . 0.50 0.50 Cys 187 A . . . . T .1.13 −0.36 . . . 0.85 1.15 Lys 188 A . . . . T . 1.13 −1.04 . . F 1.301.38 Lys 189 A . . . . T . 1.71 −1.53 * . F 1.30 2.37 Asn 190 A . . . .T . 1.17 −1.54 * . F 1.30 6.38 Glu 191 A . . . . . . 1.76 −1.47 * . F1.10 2.37 Glu 192 A . . . . . . 1.57 −1.47 . * F 1.10 2.05 Thr 193 A . .B . . . 1.52 −0.83 * * F 0.75 0.95 Val 194 A . . B . . . 0.78 −0.83 . *F 0.75 0.88 Glu 195 A . . B . . . 0.47 −0.04 . * . 0.30 0.44 Val 196 A .. B . . . 0.16 0.44 . * . −0.60 0.44 Asn 197 . . B B . . . −0.16 0.44. * . −0.60 0.85 Phe 198 . . B B . . . −0.06 0.29 . * . −0.30 0.71 Thr199 . . B B . . . −0.01 0.71 . * F −0.30 1.48 Thr 200 . . B B . . .−0.36 0.76 . * F −0.33 0.76 Thr 201 . . . . . T C 0.50 0.79 . * F 0.390.87 Pro 202 . . . . . T C 0.61 0.40 . . F 0.81 0.97 Leu 203 . . . . T T. 1.07 −0.09 * . F 1.88 1.32 Gly 204 . . . . . T C 0.78 0.19 * . F 1.201.43 Asn 205 . . . . . T C 0.50 0.31 * . F 0.93 0.91 Arg 206 . . B . . T. 0.00 0.39 * . . 0.61 1.12 Tyr 207 . . B . . T . −0.68 0.39 * * . 0.340.93 Met 208 . . B . . T . 0.13 0.64 * . . −0.08 0.41 Ala 209 . . B B .. . 0.44 0.64 * . . −0.60 0.36 Leu 210 . . B B . . . 0.14 1.14 * . .−0.60 0.31 Ile 211 . . B B . . . −0.28 0.77 * * . −0.60 0.42 Gln 212 . .B B . . . −0.92 0.64 . . . −0.60 0.60 His 213 . . B B . . . −1.21 0.83 .. . −0.60 0.51 Ser 214 . . B B . . . −0.97 0.83 . . . −0.60 0.51 Thr 215. . B B . . . −0.86 0.57 . . . −0.60 0.29 Ile 216 . . B B . . . −0.270.96 . . . −0.60 0.19 Ile 217 . . B B . . . −0.27 0.84 . . . −0.60 0.19Gly 218 . . B B . . . −1.09 0.86 * . . −0.60 0.22 Phe 219 . . B B . . .−1.49 1.01 * . . −0.60 0.24 Ser 220 . . . B . . C −1.18 1.11 * . . −0.400.29 Gln 221 . . B B . . . −0.50 0.43 * . . −0.60 0.51 Val 222 . . B B .. . 0.36 0.43 * . . −0.60 0.92 Phe 223 A . . B . . . 0.70 0.14 * . .−0.30 0.93 Glu 224 A . . B . . . 1.44 0.16 * . F −0.15 0.93 Pro 225 A A. . . . . 1.79 −0.24 * . F 0.60 2.51 His 226 A A . . . . . 1.79 −0.89 *. F 0.90 5.79 Gln 227 A A . . . . . 2.33 −1.27 * * F 0.90 5.79 Lys 228 AA . . . . . 3.14 −0.79 * * F 0.90 5.40 Lys 229 A A . B . . . 2.56−1.21 * * F 0.90 7.77 Gln 230 A A . B . . . 2.47 −1.21 . * F 0.90 4.53Thr 231 . A B B . . . 1.64 −1.23 . * F 0.90 3.04 Arg 232 . A B B . . .0.79 −0.59 * * F 0.90 1.13 Ala 233 . A B B . . . −0.14 0.06 * * F −0.150.48 Ser 234 . . B B . . . −0.40 0.34 . * . −0.30 0.23 Val 235 . . B B .. . −1.26 0.29 . * . −0.30 0.19 Val 236 . . B B . . . −1.26 0.93 . * .−0.60 0.14 Ile 237 . . B B . . . −1.71 0.91 * * . −0.60 0.15 Pro 238 . .B B . . . −1.12 0.96 . * . −0.60 0.20 Val 239 . . B B . . . −1.12 0.31. * . −0.30 0.44 Thr 240 . . B B . . . −0.27 0.06 . * F 0.15 0.84 Gly241 . . . B . . C 0.24 −0.63 . * F 1.55 0.94 Asp 242 . . . . . T C 0.54−0.63 . * F 2.40 1.26 Ser 243 . . . . . T C 0.44 −0.77 . . F 2.55 0.88Glu 244 . . . . . T C 0.44 −0.77 . * F 3.00 1.28 Gly 245 . . B . . T .0.76 −0.56 . * F 2.35 0.57 Ala 246 . . B B . . . 0.29 −0.16 . * F 1.350.74 Thr 247 . . B B . . . −0.02 0.14 . * . 0.30 0.35 Val 248 . . B B .. . 0.07 0.63 . . . −0.30 0.51 Gln 249 . . B B . . . −0.18 0.63 . * .−0.60 0.78 Leu 250 . . B B . . . −0.53 0.89 . * . −0.60 0.85 Thr 251 . .B B . . . −0.16 1.19 . * . −0.60 0.99 Pro 252 . . B B . . . −0.16 0.97. * F −0.45 0.89 Tyr 253 . . . B T . . 0.03 1.06 * * F 0.10 1.55 Phe 254. . B . . T . −0.31 0.94 * . . −0.20 0.58 Pro 255 . . . . T T . 0.200.89 * . F 0.35 0.37 Thr 256 . . . . T T . 0.51 0.84 * . F 0.35 0.31 Cys257 . . . . T T . 0.06 0.09 * . F 0.65 0.61 Gly 258 . . . . T T . −0.59−0.13 * * F 1.25 0.21 Ser 259 . . . . T T . 0.22 0.13 * . F 0.65 0.10Asp 260 . . B . . T . 0.40 −0.36 * * F 0.85 0.37 Cys 261 . . B . . T .0.76 −0.43 * * . 0.98 0.51 Ile 262 . . B . . . . 1.08 −0.86 * * . 1.360.77 Arg 263 . . B . . . . 1.11 −0.81 * * . 1.64 0.45 His 264 . . . . TT . 0.56 −0.33 * * . 2.37 1.22 Lys 265 . . . . T T . −0.30 −0.26 * * F2.80 1.30 Gly 266 . . . . T T . −0.44 −0.30 * * F 2.37 0.49 Thr 267 . .B . . T . −0.22 0.39 * * F 1.09 0.30 Val 268 . . B B . . . −0.54 0.46. * . −0.04 0.08 Val 269 . . B B . . . −0.51 0.89 . * . −0.32 0.12 Leu270 . . B B . . . −0.87 0.86 . * . −0.60 0.15 Cys 271 . . B . . T .−0.87 0.86 . . . −0.20 0.29 Pro 272 . . B . . T . −1.41 0.64 . . F −0.050.39 Gln 273 . . . . T T . −0.77 0.64 . . F 0.35 0.35 Thr 274 . . . . TT . −0.61 0.39 . . F 0.80 1.01 Gly 275 . . B . . . . −0.01 0.60 . * F−0.25 0.56 Val 276 . . B . . T . −0.16 0.60 . * . −0.20 0.50 Pro 277 . .B . . T . 0.06 0.89 . * . −0.20 0.29 Phe 278 . . B . . T . 0.06 0.40 . *. 0.14 0.49 Pro 279 . . B . . T . 0.37 0.37 . . . 0.93 1.05 Leu 280 . .B . . . . 0.76 0.13 . . F 1.22 1.09 Asp 281 . . . . T T . 1.31 −0.30 . *F 2.76 2.52 Asn 282 . . . . T T . 1.57 −0.70 . . F 3.40 2.19 Asn 283 . .. . T T . 2.06 −1.13 . . F 3.06 5.31 Lys 284 . . . . T T . 1.92 −1.39 .. F 2.85 4.91 Ser 285 . . . . . . C 2.39 −0.96 . . F 2.24 3.02 Lys 286 .. . . . T C 2.10 −0.93 . . F 2.23 1.86 Pro 287 . . . . T T . 1.29 −0.41. . F 1.77 0.98 Gly 288 . . . . T T . 1.08 0.27 . . F 1.30 0.60 Gly 289. . . . T T . 0.22 0.31 . * F 1.17 0.47 Trp 290 . . B B . . . −0.291.00 * . . −0.21 0.25 Leu 291 . . B B . . . −1.14 1.26 . . . −0.34 0.21Pro 292 . . B B . . . −1.74 1.51 . . . −0.47 0.17 Leu 293 . . B B . . .−1.70 1.77 . . . −0.60 0.14 Leu 294 . . B B . . . −2.17 1.24 . . . −0.600.22 Leu 295 . . B B . . . −2.69 1.24 . . . −0.60 0.12 Leu 296 . . B B .. . −2.73 1.50 . . . −0.60 0.12 Ser 297 . . B B . . . −3.11 1.46 . . .−0.60 0.11 Leu 298 . . B B . . . −2.61 1.27 . . . −0.60 0.13 Leu 299 A .. B . . . −2.09 1.07 . . . −0.60 0.23 Val 300 A . . B . . . −2.13 1.30 .. . −0.60 0.18 Ala 301 A . . B . . . −2.13 1.56 . . . −0.60 0.16 Thr 302A . . B . . . −2.69 1.56 . . . −0.60 0.16 Trp 303 . . B B . . . −2.471.51 . . . −0.60 0.16 Val 304 . . B B . . . −2.00 1.37 . . . −0.60 0.16Leu 305 . . B B . . . −2.03 1.30 . . . −0.60 0.11 Val 306 . . B B . . .−1.69 1.50 . . . −0.60 0.07 Ala 307 . . B B . . . −2.19 1.34 . . . −0.600.15 Gly 308 . . B B . . . −2.50 1.39 . . . −0.60 0.15 Ile 309 A . . B .. . −1.93 1.31 * * . −0.60 0.21 Tyr 310 A . . B . . . −1.01 1.59 * * .−0.60 0.21 Leu 311 A . . B . . . −0.19 1.09 * * . −0.60 0.42 Met 312 A .. B . . . 0.40 1.16 * * . −0.60 0.82 Trp 313 A . . B . . . 0.86 0.47 * *. −0.60 0.91 Arg 314 A . . B . . . 0.86 −0.29 . * . 0.45 2.16 His 315 A. . B . . . 1.14 −0.29 * . . 0.45 1.53 Glu 316 A . . B . . . 2.00−0.90 * . . 0.75 2.91 Arg 317 A A . . . . . 2.29 −1.81 * . F 0.90 2.97Ile 318 A A . . . . . 2.28 −1.33 * . F 0.90 3.15 Lys 319 . A . . T . .1.47 −1.44 * . F 1.30 2.43 Lys 320 . A . B T . . 1.20 −0.66 * * F 1.301.08 Thr 321 . A . B . . C 0.89 −0.27 * . F 0.80 2.06 Ser 322 . A . B .. C 0.47 −0.47 * * F 0.80 1.48 Phe 323 . . B B . . . 1.04 0.01 * . F0.00 1.07 Ser 324 . . B B . . . 0.19 0.50 . . F −0.30 1.07 Thr 325 . . BB . . . −0.67 0.70 . . F −0.45 0.66 Thr 326 . . B B . . . −0.57 1.00 . .F −0.45 0.63 Thr 327 . . B B . . . −0.48 0.64 . . F −0.45 0.72 Leu 328 .. B B . . . −0.67 0.69 . * F −0.45 0.78 Leu 329 . . B B . . . −0.320.89 * * F −0.45 0.38 Pro 330 . . B B . . . −0.87 0.40 * . F −0.15 0.52Pro 331 . . B B . . . −1.37 0.56 * * F −0.45 0.47 Ile 332 . . B B . . .−1.91 0.56 * * F −0.45 0.47 Lys 333 . . B B . . . −1.96 0.51 * * F −0.450.23 Val 334 . . B B . . . −1.39 0.73 . . . −0.60 0.11 Leu 335 . . B B .. . −1.39 1.06 . * . −0.60 0.24 Val 336 . . B B . . . −1.48 0.80 * * .−0.60 0.19 Val 337 . . B B . . . −0.59 1.19 * * . −0.60 0.34 Tyr 338 . .B . . T . −1.52 0.54 * . . −0.20 0.71 Pro 339 A . . . . T . −1.33 0.54 .. F −0.05 0.67 Ser 340 A . . . T T . −1.22 0.47 . * F 0.35 0.48 Glu 341A . . . . T . −0.40 0.61 . . F −0.05 0.27 Ile 342 A . . B . . . 0.420.36 . . . −0.30 0.24 Cys 343 A . . B . . . 0.36 0.43 . * . −0.60 0.24Phe 344 A . . B . . . −0.32 0.53 . * . −0.60 0.20 His 345 A . . B . . .−0.69 1.21 . * . −0.60 0.20 His 346 . . B B . . . −0.93 1.10 . * . −0.600.20 Thr 347 . . . B T . . −0.74 1.29 . * . −0.20 0.36 Ile 348 . . . B T. . −0.39 1.29 * . . −0.20 0.23 Cys 349 . . . B T . . 0.31 1.27 * . .−0.20 0.24 Tyr 350 . . . B T . . −0.36 0.77 * . . −0.20 0.29 Phe 351 . .B B . . . −1.13 1.07 * . . −0.60 0.36 Thr 352 A . . B . . . −0.82 1.07 *. . −0.60 0.56 Glu 353 A . . B . . . 0.07 0.90 * . . −0.60 0.61 Phe 354A . . B . . . 0.70 0.54 * . . −0.45 1.14 Leu 355 A . . B . . . 0.280.26 * * . −0.15 1.07 Gln 356 A . . B . . . 1.09 0.34 * * . −0.30 0.33Asn 357 . . . B T . . 1.10 0.34 * * . 0.10 0.75 His 358 . . . B . . C1.10 −0.06 * * . 0.65 1.22 Cys 359 . . . . T T . 0.94 −0.74 . * . 1.551.22 Arg 360 A . . . . T . 0.87 −0.50 * * F 1.15 0.56 Ser 361 A . . . .T . 0.06 −0.21 . * F 0.85 0.29 Glu 362 A . . . . T . 0.06 −0.03 . * F0.85 0.45 Val 363 A A . . . . . 0.13 −0.60 * * . 0.60 0.40 Ile 364 A A .. . . . 0.51 −0.60 * * . 0.60 0.59 Leu 365 A A . . . . . 0.40 −0.07 * *. 0.30 0.36 Glu 366 A A . . . . . 0.74 0.33 * . . −0.30 0.84 Lys 367 A A. . . . . 0.79 −0.31 * . F 0.60 2.38 Trp 368 A A . . . . . 1.69 −1.00 .. F 0.90 5.78 Gln 369 A A . . . . . 1.69 −1.69 . . F 0.90 6.68 Lys 370 AA . . . . . 1.91 −1.00 * . F 0.90 2.34 Lys 371 A A . . . . . 1.91−0.50 * . F 0.90 2.25 Lys 372 A A . . . . . 1.27 −1.41 * . F 0.90 2.25Ile 373 A A . . . . . 1.21 −1.20 . . . 0.75 1.11 Ala 374 . A B . . . .1.00 −0.77 . . . 0.60 0.55 Glu 375 . A B . . . . 0.10 −0.34 . . . 0.300.43 Met 376 . A B . . . . 0.06 0.30 * . . −0.30 0.45 Gly 377 . . B . .T . −0.28 0.01 * . . 0.10 0.77 Pro 378 A . . . . T . −0.20 0.43 . . .−0.20 0.47 Val 379 A . . . . T . −0.20 1.11 . . . −0.20 0.39 Gln 380 A .. . . T . −0.51 1.00 . . . −0.20 0.40 Trp 381 A A . . . . . 0.09 1.06 .. . −0.60 0.37 Leu 382 A A . . . . . 0.48 1.03 . . . −0.60 0.87 Ala 383A A . . . . . 0.73 0.39 . . . −0.15 1.00 Thr 384 A A . . . . . 1.00−0.01 * . F 0.60 1.91 Gln 385 A A . . . . . 0.41 −0.43 * . F 0.60 2.34Lys 386 A A . . . . . 0.70 −0.61 * . F 0.90 2.34 Lys 387 A A . . . . .1.56 −1.11 * . F 0.90 2.71 Ala 388 A A . . . . . 1.29 −1.60 * . F 0.903.12 Ala 389 A A . . . . . 0.74 −1.36 * . F 0.90 1.16 Asp 390 A A . . .. . 0.04 −0.71 * . F 0.75 0.43 Lys 391 A A . . . . . −0.81 0.07 * . .−0.30 0.37 Val 392 . A B . . . . −1.67 0.26 * . . −0.30 0.30 Val 393 . AB . . . . −1.38 0.44 * . . −0.60 0.15 Phe 394 . A B . . . . −0.79 0.83 *. . −0.60 0.10 Leu 395 . A B . . . . −0.79 1.23 * . . −0.60 0.22 Leu 396. A B . . . . −1.69 0.59 * * . −0.60 0.49 Ser 397 . A . . T . . −0.830.59 * . F −0.05 0.42 Asn 398 . . . . T . . −0.28 0.20 * . F 0.45 0.81Asp 399 . . . . T T . −0.43 −0.10 * . F 1.40 1.32 Val 400 . . . . T T .−0.29 −0.14 * . F 1.25 0.73 Asn 401 . . B . T T . 0.52 0.04 * * F 0.650.24 Ser 402 . . B . . T . 0.48 −0.36 * . . 0.70 0.24 Val 403 . . B . .. . 0.17 0.07 * . . 0.21 0.32 Cys 404 . . B . . T . −0.50 −0.09 * . .1.32 0.29 Asp 405 . . B . . T . 0.01 0.09 . . F 1.18 0.12 Gly 406 . . .. T T . 0.06 0.13 . . F 1.89 0.16 Thr 407 . . . . T T . 0.06 −0.51 . . F3.10 0.58 Cys 408 . . B . . T . 0.91 −0.70 . . F 2.39 0.47 Gly 409 . . .. T T . 1.23 −0.70 . . F 2.48 0.81 Lys 410 . . . . T T . 0.93 −0.70 . .F 2.17 0.56 Ser 411 . . . . . T C 1.07 −0.80 . . F 1.81 1.40 Glu 412 . .. . . . C 1.08 −0.94 . . F 1.30 2.18 Gly 413 . . . . . . C 1.74 −0.99. * F 1.64 1.46 Ser 414 . . . . . T C 2.09 −0.99 . * F 2.18 1.89 Pro 415. . . . . T C 1.74 −0.97 . * F 2.52 1.75 Ser 416 . . . . . T C 2.04−0.59 . . F 2.86 2.38 Glu 417 . . . . T T . 2.04 −0.61 . . F 3.40 3.07Asn 418 . . . . T . . 2.09 −1.00 . . F 2.86 3.32 Ser 419 . . . . T T .2.09 −1.04 . . F 2.93 3.32 Gln 420 . . . . T T . 2.09 −1.04 . . F 2.802.57 Asp 421 . . . . T T . 1.72 −0.61 . . F 2.67 2.47 Ser 422 . . . . TT . 0.91 −0.44 . . F 2.09 0.99 Ser 423 . . . . . T C 0.52 −0.14 . . F2.10 0.47 Pro 424 . . B . . T . 0.43 −0.11 . . . 1.54 0.36 Cys 425 . . B. . T . 0.04 0.31 . . . 0.73 0.34 Leu 426 . . B . . T . −0.34 0.36 . . .0.52 0.33

[0069] Among highly preferred fragments in this regard are those thatcomprise reigons of IL17RLP that combine several structural features,such as several features set out above.

[0070] In another aspect, the invention provides an isolated nucleicacid molecule comprising a polynucleotide which hybridizes understringent hybridization conditions to a portion of the polynucleotide ina nucleic acid molecule of the invention described above, for instance,the cDNA clone contained in ATCC Deposit No. 209198. By “stringenthybridization conditions” is intended overnight incubation at 42° C. ina solution comprising: 50% formamide, 5×SSC (750 mM NaCl, 75 mMtrisodium citrate), 50 mM sodium phosphate (pH 7.6), 5× Denhardt'ssolution, 10% dextran sulfate, and 20 μg/ml denatured, sheared salmonsperm DNA, followed by washing the filters in 0.1×SSC at about 65° C.

[0071] By a polynucleotide which hybridizes to a “portion” of apolynucleotide is intended a polynucleotide (either DNA or RNA)hybridizing to at least about 15 nucleotides (nt), and more preferablyat least about 20 nt, still more preferably at least about 30 nt, andeven more preferably about 30-70 (e.g., 50) nt of the referencepolynucleotide. These are useful as diagnostic probes and primers asdiscussed above and in more detail below.

[0072] By a portion of a polynucleotide of “at least 20 nt in length,”for example, is intended 20 or more contiguous nucleotides from thenucleotide sequence of the reference polynucleotide (e.g., the depositedcDNA or the nucleotide sequence as shown in FIGS. 1A, 1B, and 1C (SEQ IDNO:1)). Of course, a polynucleotide which hybridizes only to a poly Asequence (such as the 3′ terminal poly(A) tract of the IL17RLP cDNAshown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1)), or to a complementarystretch of T (or U) residues, would not be included in a polynucleotideof the invention used to hybridize to a portion of a nucleic acid of theinvention, since such a polynucleotide would hybridize to any nucleicacid molecule containing a poly (A) stretch or the complement thereof(e.g., practically any double-stranded cDNA clone).

[0073] In preferred embodiments, polynucleotides which hybridize to thereference polynucleotides disclosed herein encode polypeptides whicheither retain substantially the same biological function or activity asthe mature form of the IL17RLP polypeptide encoded by the polynucleotidesequence depicted in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) or the clonecontained in the deposit (HAPOR40).

[0074] Alternative embodiments are directed to polynucleotides whichhybridize to the reference polynucleotide (i.e., a polynucleotidesequence disclosed herein), but do not retain biological activity. Whilethese polynucleotides do not retain biological activity, they have uses,such as, for example, as probes for the polynucleotides of SEQ ID NO:1,for recovery of the polynucleotides, as diagnostic probes, and as PCRprimers.

[0075] As indicated, nucleic acid molecules of the present inventionwhich encode a IL17RLP polypeptide may include, but are not limited tothose encoding the amino acid sequence of the mature polypeptide, byitself; and the coding sequence for the mature polypeptide andadditional sequences, such as those encoding the about 19 amino acidleader or secretory sequence, such as a pre- , or pro- or prepro-proteinsequence; the coding sequence of the mature polypeptide, with or withoutthe aforementioned additional coding sequences.

[0076] Also encoded by nucleic acids of the invention are the aboveprotein sequences together with additional, non-coding sequences,including for example, but not limited to introns and non-coding 5′ and3′ sequences, such as the transcribed, non-translated sequences thatplay a role in transcription, mRNA processing, including splicing andpolyadenylation signals, for example—ribosome binding and stability ofmRNA; an additional coding sequence which codes for additional aminoacids, such as those which provide additional functionalities.

[0077] Thus, the sequence encoding the polypeptide may be fused to amarker sequence, such as a sequence encoding a peptide which facilitatespurification of the fused polypeptide. In certain preferred embodimentsof this aspect of the invention, the marker amino acid sequence is ahexa-histidine peptide, such as the tag provided in a pQE vector(QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), amongothers, many of which are commercially available. As described by Gentzand colleagues (Proc. Natl. Acad. Sci. USA 86:821-824 (1989)), forinstance, hexa-histidine provides for convenient purification of thefusion protein. The “HA” tag is another peptide useful for purificationwhich corresponds to an epitope derived from the influenza hemagglutininprotein, which has been described by Wilson and coworkers (Cell 37:767(1984)). As discussed below, other such fusion proteins include theIL17RLP fused to Fc at the N- or C-terminus.

[0078] Variant and Mutant Polynucleotides

[0079] The present invention further relates to variants of the nucleicacid molecules of the present invention, which encode portions, analogsor derivatives of the IL17RLP protein. Variants may occur naturally,such as a natural allelic variant. By an “allelic variant” is intendedone of several alternate forms of a gene occupying a given locus on achromosome of an organism (Genes II, Lewin, B., ed., John Wiley & Sons,New York (1985)). Non-naturally occurring variants may be produced usingart-known mutagenesis techniques.

[0080] Such variants include those produced by nucleotide substitutions,deletions or additions. The substitutions, deletions or additions mayinvolve one or more nucleotides. The variants may be altered in codingregions, non-coding regions, or both. Alterations in the coding regionsmay produce conservative or non-conservative amino acid substitutions,deletions or additions. Especially preferred among these are silentsubstitutions, additions and deletions, which do not alter theproperties and activities of the IL17RLP protein or portions thereof.Also especially preferred in this regard are conservative substitutions.

[0081] Most highly preferred are nucleic acid molecules encoding themature protein having the amino acid sequence shown in SEQ ID NO:2 orthe mature IL17RLP amino acid sequence encoded by the deposited cDNAclone.

[0082] Most highly preferred are nucleic acid molecules encoding theextracellular domain of the protein having the amino acid sequence shownin SEQ ID NO:2 or the extracellular domain of the IL17RLP amino acidsequence encoded by the deposited cDNA clone.

[0083] Thus, one aspect of the invention provides an isolated nucleicacid molecule comprising a polynucleotide having a nucleotide sequenceselected from the group consisting of: (a) a nucleotide sequenceencoding the IL17RLP polypeptide having the complete amino acid sequencein SEQ ID NO:2 (i.e., positions −19 to 407 of SEQ ID NO:2); (b) anucleotide sequence encoding the IL17RLP polypeptide having the completeamino acid sequence in SEQ ID NO:2 excepting the N-terminal methionine(i.e., positions −18 to 407 of SEQ ID NO:2); (c) a nucleotide sequenceencoding the predicted mature IL17RLP polypeptide having the amino acidsequence at positions 1 to 407 in SEQ ID NO:2; (d) a nucleotide sequenceencoding a polypeptide comprising the predicted extracellular domain ofthe IL17RLP polypeptide having the amino acid sequence at positions 1 to271 in SEQ ID NO:2; (e) a nucleotide sequence encoding a soluble IL17RLPpolypeptide having the predicted extracellular and intracellulardomains, but lacking the predicted transmembrane domain; (f) anucleotide sequence encoding the IL17RLP polypeptide having the completeamino acid sequence encoded by the human cDNA contained in ATCC DepositNo. 209198; (g) a nucleotide sequence encoding the IL17RLP polypeptidehaving the complete amino acid sequence excepting the N-terminalmethionine encoded by the human cDNA contained in ATCC Deposit No.209198; (h) a nucleotide sequence encoding the mature IL17RLPpolypeptide having the amino acid sequence encoded by the human cDNAcontained in ATCC Deposit No. 209198; (i) a nucleotide sequence encodingthe extracellular domain of the IL17RLP polypeptide having the aminoacid sequence encoded by the human cDNA contained in ATCC Deposit No.209198; and (j) a nucleotide sequence complementary to any of thenucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h) or (i)above.

[0084] Further embodiments of the invention include isolated nucleicacid molecules that comprise a polynucleotide having a nucleotidesequence at least 90% identical, and more preferably at least 95%, 96%,97%, 98% or 99% identical, to any of the nucleotide sequences in (a),(b), (c), (d), (e), (f), (g), (h) or (i), above, or a polynucleotidewhich hybridizes under stringent hybridization conditions to apolynucleotide in (a), (b), (c), (d), (e), (f), (g), (h) or (i), above.This polynucleotide which hybridizes does not hybridize under stringenthybridization conditions to a polynucleotide having a nucleotidesequence consisting of only A residues or of only T residues. Anadditional nucleic acid embodiment of the invention relates to anisolated nucleic acid molecule comprising a polynucleotide which encodesthe amino acid sequence of an epitope-bearing portion of a IL17RLPpolypeptide having an amino acid sequence in (a), (b), (c), (d), (e),(f), (g) or (h), above. A further nucleic acid embodiment of theinvention relates to an isolated nucleic acid molecule comprising apolynucleotide which encodes the amino acid sequence of a IL17RLPpolypeptide having an amino acid sequence which contains at least oneconservative amino acid substitution, but not more than 50 conservativeamino acid substitutions, even more preferably, not more than 40conservative amino acid substitutions, still more preferably not morethan 30 conservative amino acid substitutions, and still even morepreferably not more than 20 conservative amino acid substitutions. Ofcourse, in order of ever-increasing preference, it is highly preferablefor a polynucleotide which encodes the amino acid sequence of a IL17RLPpolypeptide to have an amino acid sequence which contains not more than10-20, 10-15, 7-15, 7-10, 5-10, 3-7, 3-5, 2-5, 1-5, 1-3, 10, 9, 8, 7, 6,5, 4, 3, 2 or 1 conservative amino acid substitutions.

[0085] The present invention also relates to recombinant vectors, whichinclude the isolated nucleic acid molecules of the present invention,and to host cells containing the recombinant vectors, as well as tomethods of making such vectors and host cells and for using them forproduction of IL17RLP polypeptides or peptides by recombinanttechniques.

[0086] By a polynucleotide having a nucleotide sequence at least, forexample, 95% “identical” to a reference nucleotide sequence encoding aIL17RLP polypeptide is intended that the nucleotide sequence of thepolynucleotide is identical to the reference sequence except that thepolynucleotide sequence may include up to five point mutations per each100 nucleotides of the reference nucleotide sequence encoding theIL17RLP polypeptide. In other words, to obtain a polynucleotide having anucleotide sequence at least 95% identical to a reference nucleotidesequence, up to 5% of the nucleotides in the reference sequence may bedeleted or substituted with another nucleotide, or a number ofnucleotides up to 5% of the total nucleotides in the reference sequencemay be inserted into the reference sequence. These mutations of thereference sequence may occur at the 5′ or 3′ terminal positions of thereference nucleotide sequence or anywhere between those terminalpositions, interspersed either individually among nucleotides in thereference sequence or in one or more contiguous groups within thereference sequence.

[0087] As a practical matter, whether any particular nucleic acidmolecule is at least 90%, 95%, 96%, 97%, 98% or 99% identical to, forinstance, the nucleotide sequence shown in FIGS. 1A, 1B, and 1C or tothe nucleotides sequence of the deposited cDNA clone can be determinedconventionally using known computer programs such as the Bestfit program(Wisconsin Sequence Analysis Package, Version 8 for Unix, GeneticsComputer Group, University Research Park, 575 Science Drive, Madison,Wis. 53711). Bestfit uses the local homology algorithm of Smith andWaterman to find the best segment of homology between two sequences(Advances in Applied Mathematics 2:482-489 (1981)). When using Bestfitor any other sequence alignment program to determine whether aparticular sequence is, for instance, 95% identical to a referencesequence according to the present invention, the parameters are set, ofcourse, such that the percentage of identity is calculated over the fulllength of the reference nucleotide sequence and that gaps in homology ofup to 5% of the total number of nucleotides in the reference sequenceare allowed. A preferred method for determing the best overall matchbetween a query sequence (a sequence of the present invention) and asubject sequence, also referred to as a global sequence alignment, canbe determined using the FASTDB computer program based on the algorithmof Brutlag and colleagues (Comp. App. Biosci. 6:237-245 (1990)). In asequence alignment the query and subject sequences are both DNAsequences. An RNA sequence can be compared by converting U's to T's. Theresult of said global sequence alignment is in percent identity.Preferred parameters used in a FASTDB alignment of DNA sequences tocalculate percent identiy are: Matrix=Unitary, k-tuple=4, MismatchPenalty=1, Joining Penalty=30, Randomization Group Length=0, CutoffScore=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or thelength of the subject nucleotide sequence, whichever is shorter.

[0088] If the subject sequence is shorter than the query sequencebecause of 5′ or 3′ deletions, not because of internal deletions, amanual correction must be made to the results. This is becuase theFASTDB program does not account for 5′ and 3′ truncations of the subjectsequence when calculating percent identity. For subject sequencestruncated at the 5′ or 3′ ends, relative to the the query sequence, thepercent identity is corrected by calculating the number of bases of thequery sequence that are 5′ and 3′ of the subject sequence, which are notmatched/aligned, as a percent of the total bases of the query sequence.Whether a nucleotide is matched/aligned is determined by results of theFASTDB sequence alignment. This percentage is then subtracted from thepercent identity, calculated by the above FASTDB program using thespecified parameters, to arrive at a final percent identity score. Thiscorrected score is what is used for the purposes of the presentinvention. Only bases outside the 5′ and 3′ bases of the subjectsequence, as displayed by the FASTDB alignment, which are notmatched/aligned with the query sequence, are calculated for the purposesof manually adjusting the percent identity score.

[0089] For example, a 90 base subject sequence is aligned to a 100 basequery sequence to determine percent identity. The deletions occur at the5′ end of the subject sequence and therefore, the FASTDB alignment doesnot show a matched/alignement of the first 10 bases at 5′ end. The 10unpaired bases represent 10% of the sequence (number of bases at the 5′and 3′ ends not matched/total number of bases in the query sequence) so10% is subtracted from the percent identity score calculated by theFASTDB program. If the remaining 90 bases were perfectly matched thefinal percent identity would be 90%. In another example, a 90 basesubject sequence is compared with a 100 base query sequence. This timethe deletions are internal deletions so that there are no bases on the5′ or 3′ of the subject sequence which are not matched/aligned with thequery. In this case the percent identity calculated by FASTDB is notmanually corrected. Once again, only bases 5′ and 3′ of the subjectsequence which are not matched/aligned with the query sequnce aremanually corrected for. No other manual corrections are to made for thepurposes of the present invention.

[0090] The present application is directed to nucleic acid molecules atleast 90%, 95%, 96%, 97%, 98% or 99% identical to the nucleic acidsequence shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) or to the nucleicacid sequence of the deposited cDNA, irrespective of whether they encodea polypeptide having IL17RLP activity. This is because even where aparticular nucleic acid molecule does not encode a polypeptide havingIL17RLP activity, one of skill in the art would still know how to usethe nucleic acid molecule, for instance, as a hybridization probe or apolymerase chain reaction (PCR) primer. Uses of the nucleic acidmolecules of the present invention that do not encode a polypeptidehaving IL17RLP activity include, inter alia, (1) isolating the IL17RLPgene or allelic variants thereof in a cDNA library; (2) in situhybridization (e.g., “FISH”) to metaphase chromosomal spreads to provideprecise chromosomal location of the IL17RLP gene, as described by Vermaand colleagues (Human Chromosomes: A Manual of Basic Techniques,Pergamon Press, New York (1988)); and Northern Blot analysis fordetecting IL17RLP mRNA expression in specific tissues.

[0091] Preferred, however, are nucleic acid molecules having sequencesat least 90%, 95%, 96%, 97%, 98% or 99% identical to the nucleic acidsequence shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) or to the nucleicacid sequence of the deposited cDNA which do, in fact, encode apolypeptide having IL17RLP protein activity. By “a polypeptide havingIL17RLP activity” is intended polypeptides exhibiting activity similar,but not necessarily identical, to an activity of the mature or solubleform of the IL17RLP protein of the invention, as measured in aparticular biological assay. For example, the IL17RLP protein of thepresent invention modulates IL-6 secretion from NIH-3T3 cells. An invitro ELISA assay which quantitates the amount of IL-6 secreted fromcells in response to treatment with cytokines or the solubleextracellular domains of cytokine receptors has been described (Yao, Z.,et al., Immunity 3:811-821 (1995)). Briefly, the assay involves platingthe target cells at a density of approximately 5×106 cells/mL in avolume of 500 μL in the wells of a 24 well flat-bottomed culture plate(Costar). The cultures are then treated with various concentrations ofthe cytokine or the soluble extracellular domain of cytokine receptor inquestion The cells are then cultured for 24 hours at 37° C. At thistime, 50 μL of supernatant is removed and assayed for the quantity ofIL-6 essentially as described by the manufacturer (Genzyme, Boston,Mass.). IL-6 levels are then calculated by reference to a standard curveconstructed with recombinant IL-17 cytokine. Such activity is useful fordetermining the level of IL17RLP-mediated IL-6 secretion.

[0092] IL17RLP protein modulates immune system cell proliferation anddifferentiation in a dose-dependent manner in the above-described assay.Thus, “a polypeptide having IL17RLP protein activity” includespolypeptides that also exhibit any of the same stimulatory activities inthe above-described assays in a dose-dependent manner. Although thedegree of dose-dependent activity need not be identical to that of theIL17RLP protein, preferably, “a polypeptide having IL17RLP proteinactivity” will exhibit substantially similar dose-dependence in a givenactivity as compared to the IL17RLP protein (i.e., the candidatepolypeptide will exhibit greater activity or not more than about 25-foldless and, preferably, not more than about tenfold less activity relativeto the reference IL17RLP protein).

[0093] Lymphocyte proliferation is another in vitro assay which may beperformed to determine the activity of IL17RLP and soluble,extracellular domains of IL17RLP. For example, Yao and colleagues(Immunity 3:811-821 (1995)) have recently described an in vitro assayfor determining the effects of various cytokines and soluble cytokinereceptors on the proliferation of murine leukocytes. Briefly, lymphoidorgans are harvested aseptically, lymphocytes are isolated from theharvested organs, and the resulting collection of lymphoid cells aresuspended in standard culture medium as described by Fanslow andcoworkers (J. Immunol. 147:535-5540 (1991)). The lymphoid cellsuspensions may then be divided into several different subclasses oflymphoid cells including splenic T-cells, lymph node B-cells, CD4+ andCD8+ T-cells, and mature adult thymocytes. For splenic T-cells, spleencell suspensions (200×106 cells) are incubated with CD11b mAb and classII MHC mAb for 30 min at 4° C., loaded on a T-cell purification column(Pierce, Rockford, Ill.), and the T-cells eluted according to themanufacturer's instructions. Using this method, purity of the resultingT-cell populations should be >95% CD3+ and <1% sIgM+. For purificationof lymph node subsets, B-cells are removed from by adherence to tissueculture dishes previously coated with goat anti-mouse IgG (10 μg/mL).Remaining cells were then incubated with anti-CD4 or anti-CD8 for 30 minat 4° C. then washed and placed on tissue culture dishes previouslycoated with goat anti-rat IgG (20 μg/mL). After 45 min, nonadherentcells are removed and tested for purity by flow cytometry. CD4 andsurface Ig-depleted cells should be >90% TCR-??, CD8+, whereas CD8 andsurface Ig-depleted cells should be >95% TCR-??, CD4+. Finally, toenrich for mature adult thymocytes, cells are suspended at 108/mL in 10%anti-HSA and 10% low tox rabbit complement (Cedarlane, Ontario, Canada),incubated for 45 min at 37° C., and remaining viable cells isolated overFicoll-Hypaque (Pharmacia, Piscataway, N.J.). This procedure shouldyield between 90 and 95% CD3hi cells that are either CD4+8− or CD4−8+.

[0094] To analyze the proliferative response of the above-describedprimary cell cultures, in vitro proliferation assays are set up in roundbottom or flat bottom 96-well plates using 0.5-1.5×105 cells/well. Forstimulation, T-cells are incubated with suboptimal concentrations(0.25-0.5 μg/mL) of Con A (Sigma, St. Louis, Mo.), PHA (0.25-0.5%;Difco, Detroit, Mich.), immobilized anti-CD3, or immobilizedanti-TCR-??. Anti-CD3 and anti-TCR-?? are immobilized for >2 hours at37° C. before the addition of effector cells. Incubations are done inthe presence and absence of fixed CV-1/EBNA cells transfected withIL17RLP, muteins thereof, a control vector, or a control antigen such asrCD40L (Armitage, et al., Nature 357:80 (1992)); Spriggs, et al., J.Exp. Med. 176:1543 (1992)). Surface expression of CD40L is monitored byflow cytometry using a human CD40-Fc fusion protein. Cell cultures arepulsed overnight with [3H]-thymidine (1 μCi/well) for the last 18 hoursof a 3 day culture. Labeled cultures are then harvested on a 96-wellInotech harvester and radioactive counts detected using a scintillationcounter.

[0095] Like other cytokine receptors, IL17RLP exhibits activity onleukocytes including for example monocytes, lymphocytes and neutrophils.For this reason IL17RLP is active in directing the proliferation anddifferentiation of these cell types. Such activity is useful for immuneenhancement or suppression, myeloprotection, stem cell mobilization,acute and chronic inflammatory control and treatment of leukemia. Assaysfor measuring such activity are well known in the art (Peters, et al.,Immun. Today 17:273 (1996); Young, et al., J. Exp. Med. 182:1111 (1995);Caux, et al., Nature 390:258 (1992); and Santiago-Schwarz, et al., Adv.Exp. Med. Biol. 378:7 (1995).

[0096] Of course, due to the degeneracy of the genetic code, one ofordinary skill in the art will immediately recognize that a large numberof the nucleic acid molecules having a sequence at least 90%, 95%, 96%,97%, 98%, or 99% identical to the nucleic acid sequence of the depositedcDNA or the nucleic acid sequence shown in FIGS. 1A, 1B, and 1C (SEQ IDNO:1) will encode a polypeptide “having IL17RLP protein activity.” Infact, since degenerate variants of these nucleotide sequences all encodethe same polypeptide, this will be clear to the skilled artisan evenwithout performing the above described comparison assay. It will befurther recognized in the art that, for such nucleic acid molecules thatare not degenerate variants, a reasonable number will also encode apolypeptide having IL17RLP protein activity. This is because the skilledartisan is fully aware of amino acid substitutions that are either lesslikely or not likely to significantly effect protein function (e.g.,replacing one aliphatic amino acid with a second aliphatic amino acid),as further described below.

[0097] Vectors and Host Cells

[0098] The present invention also relates to vectors which include theisolated DNA molecules of the present invention, host cells which aregenetically engineered with the recombinant vectors, and the productionof IL17RLP polypeptides or fragments thereof by recombinant techniques.The vector may be, for example, a phage, plasmid, viral or retroviralvector. Retroviral vectors may be replication competent or replicationdefective. In the latter case, viral propagation generally will occuronly in complementing host cells.

[0099] The polynucleotides may be joined to a vector containing aselectable marker for propagation in a host. Generally, a plasmid vectoris introduced in a precipitate, such as a calcium phosphate precipitate,or in a complex with a charged lipid. If the vector is a virus, it maybe packaged in vitro using an appropriate packaging cell line and thentransduced into host cells.

[0100] The DNA insert should be operatively linked to an appropriatepromoter, such as the phage lambda PL promoter, the E. coli lac, trp,phoA and tac promoters, the SV40 early and late promoters and promotersof retroviral LTRs, to name a few. Other suitable promoters will beknown to the skilled artisan. The expression constructs will furthercontain sites for transcription initiation, termination and, in thetranscribed region, a ribosome binding site for translation. The codingportion of the transcripts expressed by the constructs will preferablyinclude a translation initiating codon at the beginning and atermination codon (UAA, UGA or UAG) appropriately positioned at the endof the polypeptide to be translated.

[0101] As indicated, the expression vectors will preferably include atleast one selectable marker. Such markers include dihydrofolatereductase, G418 or neomycin resistance for eukaryotic cell culture andtetracycline, kanamycin or ampicillin resistance genes for culturing inE. coli and other bacteria. Representative examples of appropriate hostsinclude, but are not limited to, bacterial cells, such as E. coli,Streptomyces and Salmonella typhimurium cells; fungal cells, such asyeast cells; insect cells such as Drosophila S2 and Spodoptera Sf9cells; animal cells such as CHO, COS, 293 and Bowes melanoma cells; andplant cells. Appropriate culture mediums and conditions for theabove-described host cells are known in the art.

[0102] Vectors preferred for use in bacteria include pHE4-5, pQE70,pQE60 and pQE-9 (QIAGEN, Inc., supra); pBS vectors, Phagescript vectors,Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A (Stratagene); andptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia). Among preferredeukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1, and pSG(Stratagene); and pSVK3, pBPV, pMSG and pSVL (Pharmacia). Other suitablevectors will be readily apparent to the skilled artisan.

[0103] Introduction of the construct into the host cell can be effectedby calcium phosphate transfection, DEAE-dextran mediated transfection,cationic lipid-mediated transfection, electroporation, transduction,infection or other methods. Such methods are described in many standardlaboratory manuals (for example, Davis, et al., Basic Methods InMolecular Biology (1986)).

[0104] The polypeptide may be expressed in a modified form, such as afusion protein, and may include not only secretion signals, but alsoadditional heterologous functional regions. For instance, a region ofadditional amino acids, particularly charged amino acids, may be addedto the N-terminus of the polypeptide to improve stability andpersistence in the host cell, during purification, or during subsequenthandling and storage. Also, peptide moieties may be added to thepolypeptide to facilitate purification. Such regions may be removedprior to final preparation of the polypeptide. The addition of peptidemoieties to polypeptides to engender secretion or excretion, to improvestability and to facilitate purification, among others, are familiar androutine techniques in the art. A preferred fusion protein comprises aheterologous region from immunoglobulin that is useful to stabilize andpurify proteins. For example, EP-A-O 464 533 (Canadian counterpart2045869) discloses fusion proteins comprising various portions ofconstant region of immunoglobulin molecules together with another humanprotein or part thereof. In many cases, the Fc part in a fusion proteinis thoroughly advantageous for use in therapy and diagnosis and thusresults, for example, in improved pharmacokinetic properties (EP-A 0232262). On the other hand, for some uses it would be desirable to be ableto delete the Fc part after the fusion protein has been expressed,detected and purified in the advantageous manner described. This is thecase when Fc portion proves to be a hindrance to use in therapy anddiagnosis, for example when the fusion protein is to be used as antigenfor immunizations. In drug discovery, for example, human proteins, suchas hIL-5, have been fused with Fc portions for the purpose ofhigh-throughput screening assays to identify antagonists of hIL-5(Bennett, D., et al., J. Molecular Recognition 8:52-58 (1995); Johanson,K., et al., J. Biol. Chem. 270:9459-9471 (1995)).

[0105] The IL17RLP protein can be recovered and purified fromrecombinant cell cultures by well-known methods including ammoniumsulfate or ethanol precipitation, acid extraction, anion or cationexchange chromatography, phosphocellulose chromatography, hydrophobicinteraction chromatography, affinity chromatography, hydroxylapatitechromatography and lectin chromatography. Most preferably, highperformance liquid chromatography (“HPLC”) is employed for purification.Polypeptides of the present invention include: products purified fromnatural sources, including bodily fluids, tissues and cells, whetherdirectly isolated or cultured; products of chemical syntheticprocedures; and products produced by recombinant techniques from aprokaryotic or eukaryotic host, including, for example, bacterial,yeast, higher plant, insect and mammalian cells. Depending upon the hostemployed in a recombinant production procedure, the polypeptides of thepresent invention may be glycosylated or may be non-glycosylated. Inaddition, polypeptides of the invention may also include an initialmodified methionine residue, in some cases as a result of host-mediatedprocesses. Thus, it is well known in the art that the N-terminalmethionine encoded by the translation initiation codon generally isremoved with high efficiency from any protein after translation in alleukaryotic cells. While the N-terminal methionine on most proteins alsois efficiently removed in most prokaryotes, for some proteins thisprokaryotic removal process is inefficient, depending on the nature ofthe amino acid to which the N-terminal methionine is covalently linked.

Polypeptides and Fragments

[0106] The invention further provides an isolated IL17RLP polypeptidehaving the amino acid sequence encoded by the deposited cDNA, or theamino acid sequence in SEQ ID NO:2, or a peptide or polypeptidecomprising a portion of the above polypeptides.

[0107] Variant and Mutant Polypeptides

[0108] To improve or alter the characteristics of IL17RLP polypeptides,protein engineering may be employed. Recombinant DNA technology known tothose skilled in the art can be used to create novel mutant proteins ormuteins including single or multiple amino acid substitutions,deletions, additions or fusion proteins. Such modified polypeptides canshow, e.g., enhanced activity or increased stability. In addition, theymay be purified in higher yields and show better solubility than thecorresponding natural polypeptide, at least under certain purificationand storage conditions.

[0109] N-Terminal and C-Terminal Deletion Mutants

[0110] For instance, for many proteins, including the extracellulardomain of a membrane associated protein or the mature form(s) of asecreted protein, it is known in the art that one or more amino acidsmay be deleted from the N-terminus or C-terminus without substantialloss of biological function. For instance, Ron and colleagues (J. Biol.Chem., 268:2984-2988 (1993)) reported modified KGF proteins that hadheparin binding activity even if 3, 8, or 27 N-terminal amino acidresidues were missing. In the present case, since the protein of theinvention is a member of the interleukin (IL)-17 receptor polypeptidefamily, deletions of N-terminal amino acids up to the cysteine atposition 5 of SEQ ID NO:2 may retain some biological activity such asligand binding or modulation of target cell activities. Polypeptideshaving further N-terminal deletions including the cysteine residue atposition 5 in SEQ ID NO:2 would not be expected to retain suchbiological activities because it is known that this residue in themurine IL-17 receptor polypeptide is likely required for forming adisulfide bridge to provide structural stability which is needed forligand binding and the initiation of the appropriate signal transductionpathways.

[0111] However, even if deletion of one or more amino acids from theN-terminus of a protein results in modification of loss of one or morebiological functions of the protein, other biological activities maystill be retained. Thus, the ability of the shortened protein to induceand/or bind to antibodies which recognize the complete, mature orextracellular domain of the protein generally will be retained when lessthan the majority of the residues of the complete, mature orextracellular domain of the protein are removed from the N-terminus.Whether a particular polypeptide lacking N-terminal residues of acomplete protein retains such immunologic activities can readily bedetermined by routine methods described herein and otherwise known inthe art.

[0112] Accordingly, the present invention further provides polypeptideshaving one or more residues deleted from the amino terminus of the aminoacid sequence of the IL17RLP shown in SEQ ID NO:2, up to the cysteineresidue at position number 5, and polynucleotides encoding suchpolypeptides. In particular, the present invention provides polypeptidescomprising the amino acid sequence of residues n¹−407 of SEQ ID NO:2,where n¹ is an integer in the range of −19 to 5, and 5 is the positionof the first residue from the N-terminus of the complete IL17RLPpolypeptide (shown in SEQ ID NO:2) believed to be required for ligandbinding activity of the IL17RLP protein.

[0113] More in particular, the invention provides polynucleotidesencoding polypeptides having the amino acid sequence of residues of−18-407, −17-407, −16-407, −15-407, −14-407, −13-407, −12-407, −11-407,−10-407, −9-407, −8-407, −7-407, −6-407, −5-407, −4-407, −3-407, −2-407,−1-407, 1-407, 2-407, 3-407, 4-407, and 5-407 of SEQ ID NO:2.Polynucleotides encoding these polypeptides also are provided.

[0114] Similarly, many examples of biologically functional C-terminaldeletion muteins are known. For instance, Interferon gamma shows up toten times higher activities by deleting 8-10 amino acid residues fromthe carboxy terminus of the protein (Dobeli, et al., J. Biotechnology7:199-216 (1988)). In the present case, since the protein of theinvention is a member of the interleukin (IL)-17 receptor polypeptidefamily, deletions of C-terminal amino acids up to the cysteine atposition 340 of SEQ ID NO:2 may retain some biological activity such asligand-binding. Polypeptides having further C-terminal deletionsincluding the cysteine residue at position 340 of SEQ ID NO:2 would notbe expected to retain such biological activities because it is knownthat this residue in the murine IL-17 receptor polypeptide is likelyrequired for forming a disulfide bridge to provide structural stabilitywhich is needed for receptor binding and signal transduction.

[0115] However, even if deletion of one or more amino acids from theC-terminus of a protein results in modification of loss of one or morebiological functions of the protein, other biological activities maystill be retained. Thus, the ability of the shortened protein to induceand/or bind to antibodies which recognize the complete, mature orextracellular domain of the protein generally will be retained when lessthan the majority of the residues of complete, mature or extracellulardomain of the protein are removed from the C-terminus. Whether aparticular polypeptide lacking C-terminal residues of a complete proteinretains such immunologic activities can readily be determined by routinemethods described herein and otherwise known in the art.

[0116] Accordingly, the present invention further provides polypeptideshaving one or more residues from the carboxy terminus of the amino acidsequence of the IL17RLP shown in SEQ ID NO:2, up to the cysteine residueat position 340 of SEQ ID NO:2, and polynucleotides encoding suchpolypeptides. In particular, the present invention provides polypeptideshaving the amino acid sequence of residues −19-m¹ of the amino acidsequence in SEQ ID NO:2, where m¹ is any integer in the range of 340 to407, and residue 340 is the position of the first residue from theC-terminus of the complete IL17RLP polypeptide (shown in SEQ ID NO:2)believed to be required for the IL17RLP protein to transfer itsextracellular signal to the interior of the cell.

[0117] More in particular, the invention provides polynucleotidesencoding polypeptides having the amino acid sequence of residues−19-340, −19-341, −19-342, −19-343, −19-344, −19-345, −19-346, −19-347,−19-348, −19-349, −19-350, −19-351, −19-352, −19-353, −19-354, −19-355,−19-356, −19-357, −19-358, −19-359, −19-360, −19-361, −19-362, −19-363,−19-364, −19-365, −19-366, −19-367, −19-368, −19-369, −19-370, −19-371,−19-372, −19-373, −19-374, −19-375, −19-376, −19-377, −19-378, −19-379,−19-380, −19-381, −19-382, −19-383, −19-384, −19-385, −19-386, −19-387,−19-388, −19-389, −19-390, −19-391, −19-392, −19-393, −19-394, −19-395,−19-396, −19-397, −19-398, −19-399, −19-400, −19-401, −19-402, −19-403,−19-404, −19-405, −19-406, and −19-407 of SEQ ID NO:2. Polynucleotidesencoding these polypeptides also are provided.

[0118] The invention also provides polypeptides having one or more aminoacids deleted from both the amino and the carboxyl termini, which may bedescribed generally as having residues n¹-m¹ of SEQ ID NO:2, where n¹and m¹ are integers as described above.

[0119] Also included are a nucleotide sequence encoding a polypeptideconsisting of a portion of the complete IL17RLP amino acid sequenceencoded by the cDNA clone contained in ATCC Deposit No. 209198, wherethis portion excludes from 1 to about 23 amino acids from the aminoterminus of the complete amino acid sequence encoded by the cDNA clonecontained in ATCC Deposit No. 209198, or from 1 to about 67 amino acidsfrom the carboxy terminus, or any combination of the above aminoterminal and carboxy terminal deletions, of the complete amino acidsequence encoded by the cDNA clone contained in ATCC Deposit No. 209198.Polynucleotides encoding all of the above deletion mutant polypeptideforms also are provided.

[0120] As mentioned above, even if deletion of one or more amino acidsfrom the N-terminus of a protein results in modification of loss of oneor more biological functions of the protein, other biological activitiesmay still be retained. Thus, the ability of the shortened IL17RLP muteinto induce and/or bind to antibodies which recognize the complete ormature of the protein generally will be retained when less than themajority of the residues of the complete or mature protein are removedfrom the N-terminus. Whether a particular polypeptide lacking N-terminalresidues of a complete protein retains such immunologic activities canreadily be determined by routine methods described herein and otherwiseknown in the art. It is not unlikely that a IL17RLP mutein with a largenumber of deleted N-terminal amino acid residues may retain somebiological or immungenic activities. In fact, peptides composed of asfew as six IL17RLP amino acid residues may often evoke an immuneresponse.

[0121] Accordingly, the present invention further provides polypeptideshaving one or more residues deleted from the amino terminus of theIL17RLP amino acid sequence shown in SEQ ID NO:2, up to the asparticacid residue at position number 421 and polynucleotides encoding suchpolypeptides. In particular, the present invention provides polypeptidescomprising the amino acid sequence of residues n²−426 of FIGS. 1A, 1B,and 1C (SEQ ID NO:2), where n² is an integer in the range of 2 to 421,and 422 is the position of the first residue from the N-terminus of thecomplete IL17RLP polypeptide believed to be required for at leastimmunogenic activity of the IL17RLP protein.

[0122] More in particular, the invention provides polynucleotidesencoding polypeptides comprising, or alternatively consisting of, theamino acid sequence of residues of S-2 to L-426; L-3 to L-426; V-4 toL-426; L-5 to L-426; L-6 to L-426; S-7 to L-426; L-8 to L-426; A-9 toL-426; A-10 to L-426; L-11 to L-426; C-12 to L-426; R-13 to L-426; S-14to L-426; A-15 to L-426; V-16 to L-426; P-17 to L-426; R-18 to L-426;E-19 to L-426; P-20 to L-426; T-21 to L-426; V-22 to L-426; Q-23 toL-426; C-24 to L-426; G-25 to L-426; S-26 to L-426; E-27 to L-426; T-28to L-426; G-29 to L-426; P-30 to L-426; S-31 to L-426; P-32 to L-426;E-33 to L-426; W-34 to L-426; M-35 to L-426; L-36 to L-426; Q-37 toL-426; H-38 to L-426; D-39 to L-426; L-40 to L-426; I-41 to L-426; P-42to L-426; G-43 to L-426; D-44 to L-426; L-45 to L-426; R-46 to L-426;D-47 to L-426; L-48 to L-426; R-49 to L-426; V-50 to L-426; E-51 toL-426; P-52 to L-426; V-53 to L-426; T-54 to L-426; T-55 to L-426; S-56to L-426; V-57 to L-426; A-58 to L-426; T-59 to L-426; G-60 to L-426;D-61 to L-426; Y-62 to L-426; S-63 to L-426; I-64 to L-426; L-65 toL-426; M-66 to L-426; N-67 to L-426; V-68 to L-426; S-69 to L-426; W-70to L-426; V-71 to L-426; L-72 to L-426; R-73 to L-426; A-74 to L-426;D-75 to L-426; A-76 to L-426; S-77 to L-426; I-78 to L-426; R-79 toL-426; L-80 to L-426; L-81 to L-426; K-82 to L-426; A-83 to L-426; T-84to L-426; K-85 to L-426; I-86 to L-426; C-87 to L-426; V-88 to L-426;T-89 to L-426; G-90 to L-426; K-91 to L-426; S-92 to L-426; N-93 toL-426; F-94 to L-426; Q-95 to L-426; S-96 to L-426; Y-97 to L-426; S-98to L-426; C-99 to L-426; V-100 to L-426; R-101 to L-426; C-102 to L-426;N-103 to L-426; Y-104 to L-426; T-105 to L-426; E-106 to L-426; A-107 toL-426; F-108 to L-426; Q-109 to L-426; T-110 to L-426; Q-111 to L-426;T-112 to L-426; R-113 to L-426; P-114 to L-426; S-115 to L-426; G-116 toL-426; G-117 to L-426; K-118 to L-426; W-119 to L-426; T-120 to L-426;F-121 to L-426; S-122 to L-426; Y-123 to L-426; I-124 to L-426; G-125 toL-426; F-126 to L-426; P-127 to L-426; V-128 to L-426; E-129 to L-426;L-130 to L-426; N-131 to L-426; T-132 to L-426; V-133 to L-426; Y-134 toL-426; F-135 to L-426; I-136 to L-426; G-137 to L-426; A-138 to L-426;H-139 to L-426; N-140 to L-426; I-141 to L-426; P-142 to L-426; N-143 toL-426; A-144 to L-426; N-145 to L-426; M-146 to L-426; N-147 to L-426;E-148 to L-426; D-149 to L-426; G-150 to L-426; P-151 to L-426; S-152 toL-426; M-153 to L-426; S-154 to L-426; V-155 to L-426; N-156 to L-426;F-157 to L-426; T-158 to L-426; S-159 to L-426; P-160 to L-426; G-161 toL-426; C-162 to L-426; L-163 to L-426; D-164 to L-426; H-165 to L-426;I-166 to L-426; M-167 to L-426; K-168 to L-426; Y-169 to L-426; K-170 toL-426; K-171 to L-426; K-172 to L-426; C-173 to L-426; V-174 to L-426;K-175 to L-426; A-176 to L-426; G-177 to L-426; S-178 to L-426; L-179 toL-426; W-180 to L-426; D-181 to L-426; P-182 to L-426; N-183 to L-426;I-184 to L-426; T-185 to L-426; A-186 to L-426; C-187 to L-426; K-188 toL-426; K-189 to L-426; N-190 to L-426; E-191 to L-426; E-192 to L-426;T-193 to L-426; V-194 to L-426; E-195 to L-426; V-196 to L-426; N-197 toL-426; F-198 to L-426; T-199 to L-426; T-200 to L-426; T-201 to L-426;P-202 to L-426; L-203 to L-426; G-204 to L-426; N-205 to L-426; R-206 toL-426; Y-207 to L-426; M-208 to L-426; A-209 to L-426; L-210 to L-426;I-211 to L-426; Q-212 to L-426; H-213 to L-426; S-214 to L-426; T-215 toL-426; I-216 to L-426; I-217 to L-426; G-218 to L-426; F-219 to L-426;S-220 to L-426; Q-221 to L-426; V-222 to L-426; F-223 to L-426; E-224 toL-426; P-225 to L-426; H-226 to L-426; Q-227 to L-426; K-228 to L-426;K-229 to L-426; Q-230 to L-426; T-231 to L-426; R-232 to L-426; A-233 toL-426; S-234 to L-426; V-235 to L-426; V-236 to L-426; I-237 to L-426;P-238 to L-426; V-239 to L-426; T-240 to L-426; G-241 to L-426; D-242 toL-426; S-243 to L-426; E-244 to L-426; G-245 to L-426; A-246 to L-426;T-247 to L-426; V-248 to L-426; Q-249 to L-426; L-250 to L-426; T-251 toL-426; P-252 to L-426; Y-253 to L-426; F-254 to L-426; P-255 to L-426;T-256 to L-426; C-257 to L-426; G-258 to L-426; S-259 to L-426; D-260 toL-426; C-261 to L-426; I-262 to L-426; R-263 to L-426; H-264 to L-426;K-265 to L-426; G-266 to L-426; T-267 to L-426; V-268 to L-426; V-269 toL-426; L-270 to L-426; C-271 to L-426; P-272 to L-426; Q-273 to L-426;T-274 to L-426; G-275 to L-426; V-276 to L-426; P-277 to L-426; F-278 toL-426; P-279 to L-426; L-280 to L-426; D-281 to L-426; N-282 to L-426;N-283 to L-426; K-284 to L-426; S-285 to L-426; K-286 to L-426; P-287 toL-426; G-288 to L-426; G-289 to L-426; W-290 to L-426; L-291 to L-426;P-292 to L-426; L-293 to L-426; L-294 to L-426; L-295 to L-426; L-296 toL-426; S-297 to L-426; L-298 to L-426; L-299 to L-426; V-300 to L-426;A-301 to L-426; T-302 to L-426; W-303 to L-426; V-304 to L-426; L-305 toL-426; V-306 to L-426; A-307 to L-426; G-308 to L-426; I-309 to L-426;Y-310 to L-426; L-311 to L-426; M-312 to L-426; W-313 to L-426; R-314 toL-426; H-315 to L-426; E-316 to L-426; R-317 to L-426; I-318 to L-426;K-319 to L-426; K-320 to L-426; T-321 to L-426; S-322 to L-426; F-323 toL-426; S-324 to L-426; T-325 to L-426; T-326 to L-426; T-327 to L-426;L-328 to L-426; L-329 to L-426; P-330 to L-426; P-331 to L-426; I-332 toL-426; K-333 to L-426; V-334 to L-426; L-335 to L-426; V-336 to L-426;V-337 to L-426; Y-338 to L-426; P-339 to L-426; S-340 to L-426; E-341 toL-426; I-342 to L-426; C-343 to L-426; F-344 to L-426; H-345 to L-426;H-346 to L-426; T-347 to L-426; I-348 to L-426; C-349 to L-426; Y-350 toL-426; F-351 to L-426; T-352 to L-426; E-353 to L-426; F-354 to L-426;L-355 to L-426; Q-356 to L-426; N-357 to L-426; H-358 to L-426; C-359 toL-426; R-360 to L-426; S-361 to L-426; E-362 to L-426; V-363 to L-426;I-364 to L-426; L-365 to L-426; E-366 to L-426; K-367 to L-426; W-368 toL-426; Q-369 to L-426; K-370 to L-426; K-371 to L-426; K-372 to L-426;I-373 to L-426; A-374 to L-426; E-375 to L-426; M-376 to L-426; G-377 toL-426; P-378 to L-426; V-379 to L-426; Q-380 to L-426; W-381 to L-426;L-382 to L-426; A-383 to L-426; T-384 to L-426; Q-385 to L-426; K-386 toL-426; K-387 to L-426; A-388 to L-426; A-389 to L-426; D-390 to L-426;K-391 to L-426; V-392 to L-426; V-393 to L-426; F-394 to L-426; L-395 toL-426; L-396 to L-426; S-397 to L-426; N-398 to L-426; D-399 to L-426;V-400 to L-426; N-401 to L-426; S-402 to L-426; V-403 to L-426; C-404 toL-426; D-405 to L-426; G-406 to L-426; T-407 to L-426; C-408 to L-426;G-409 to L-426; K-410 to L-426; S-411 to L-426; E-412 to L-426; G-413 toL-426; S-414 to L-426; P-415 to L-426; S-416 to L-426; E-417 to L-426;N-418 to L-426; S-419 to L-426; Q-420 to L-426; and D-421 to L-426 ofthe IL17RLP amino acid sequence shown in FIGS. 1A, 1B, and 1C (which isidentical to the sequence shown as SEQ ID NO:2, with the exception thatthe amino acid residues in FIGS. 1A, 1B, and 1C are numberedconsecutively from 1 through 426 from the N-terminus to the C-terminus,while the amino acid residues in SEQ ID NO:2 are numbered consecutivelyfrom −19 through 406 to reflect the position of the predicted signalpeptide). Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

[0123] Also as mentioned above, even if deletion of one or more aminoacids from the C-terminus of a protein results in modification of lossof one or more biological functions of the protein, other biologicalactivities may still be retained. Thus, the ability of the shortenedIL17RLP mutein to induce and/or bind to antibodies which recognize thecomplete or mature of the protein generally will be retained when lessthan the majority of the residues of the complete or mature protein areremoved from the C-terminus. Whether a particular polypeptide lackingC-terminal residues of a complete protein retains such immunologicactivities can readily be determined by routine methods described hereinand otherwise known in the art. It is not unlikely that a IL17RLP muteinwith a large number of deleted C-terminal amino acid residues may retainsome biological or immungenic activities. In fact, peptides composed ofas few as six IL17RLP amino acid residues may often evoke an immuneresponse.

[0124] Accordingly, the present invention further provides polypeptideshaving one or more residues deleted from the carboxy terminus of theamino acid sequence of the IL17RLP shown in SEQ ID NO:2, up to theleucine residue at position number 6, and polynucleotides encoding suchpolypeptides. In particular, the present invention provides polypeptidescomprising the amino acid sequence of residues 1-m² of SEQ ID NO:2,where m² is an integer in the range of 6 to 426, and 6 is the positionof the first residue from the C-terminus of the complete IL17RLPpolypeptide believed to be required for at least immunogenic activity ofthe IL17RLP protein.

[0125] More in particular, the invention provides polynucleotidesencoding polypeptides comprising, or alternatively consisting of, theamino acid sequence of residues M-1 to C-425; M-1 to P-424; M-1 toS-423; M-1 to S-422; M-1 to D-421; M-1 to Q-420; M-1 to S-419; M-1 toN-418; M-1 to E-417; M-1 to S-416; M-1 to P-415; M-1 to S-414; M-1 toG-413; M-1 to E-412; M-1 to S-411; M-1 to K-410; M-1 to G-409; M-1 toC-408; M-1 to T-407; M-1 to G-406; M-1 to D-405; M-1 to C-404; M-1 toV-403; M-1 to S-402; M-1 to N-401; M-1 to V-400; M-1 to D-399; M-1 toN-398; M-1 to S-397; M-1 to L-396; M-1 to L-395; M-1 to F-394; M-1 toV-393; M-1 to V-392; M-1 to K-391; M-1 to D-390; M-1 to A-389; M-1 toA-388; M-1 to K-387; M-1 to K-386; M-1 to Q-385; M-1 to T-384; M-1 toA-383; M-1 to L-382; M-1 to W-381; M-1 to Q-380; M-1 to V-379; M-1 toP-378; M-1 to G-377; M-1 to M-376; M-1 to E-375; M-1 to A-374; M-1 toI-373; M-1 to K-372; M-1 to K-371; M-1 to K-370; M-1 to Q-369; M-1 toW-368; M-1 to K-367; M-1 to E-366; M-1 to L-365; M-1 to I-364; M-1 toV-363; M-1 to E-362; M-1 to S-361; M-1 to R-360; M-1 to C-359; M-1 toH-358; M-1 to N-357; M-1 to Q-356; M-1 to L-355; M-1 to F-354; M-1 toE-353; M-1 to T-352; M-1 to F-351; M-1 to Y-350; M-1 to C-349; M-1 toI-348; M-1 to T-347; M-1 to H-346; M-1 to H-345; M-1 to F-344; M-1 toC-343; M-1 to I-342; M-1 to E-341; M-1 to S-340; M-1 to P-339; M-1 toY-338; M-1 to V-337; M-1 to V-336; M-1 to L-335; M-1 to V-334; M-1 toK-333; M-1 to I-332; M-1 to P-331; M-1 to P-330; M-1 to L-329; M-1 toL-328; M-1 to T-327; M-1 to T-326; M-1 to T-325; M-1 to S-324; M-1 toF-323; M-1 to S-322; M-1 to T-321; M-1 to K-320; M-1 to K-319; M-1 toI-318; M-1 to R-317; M-1 to E-316; M-1 to H-315; M-1 to R-314; M-1 toW-313; M-1 to M-312; M-1 to L-311; M-1 to Y-310; M-1 to I-309; M-1 toG-308; M-1 to A-307; M-1 to V-306; M-1 to L-305; M-1 to V-304; M-1 toW-303; M-1 to T-302; M-1 to A-301; M-1 to V-300; M-1 to L-299; M-1 toL-298; M-1 to S-297; M-1 to L-296; M-1 to L-295; M-1 to L-294; M-1 toL-293; M-1 to P-292; M-1 to L-291; M-1 to W-290; M-1 to G-289; M-1 toG-288; M-1 to P-287; M-1 to K-286; M-1 to S-285; M-1 to K-284; M-1 toN-283; M-1 to N-282; M-1 to D-281; M-1 to L-280; M-1 to P-279; M-1 toF-278; M-1 to P-277; M-1 to V-276; M-1 to G-275; M-1 to T-274; M-1 toQ-273; M-1 to P-272; M-1 to C-271; M-1 to L-270; M-1 to V-269; M-1 toV-268; M-1 to T-267; M-1 to G-266; M-1 to K-265; M-1 to H-264; M-1 toR-263; M-1 to I-262; M-1 to C-261; M-1 to D-260; M-1 to S-259; M-1 toG-258; M-1 to C-257; M-1 to T-256; M-1 to P-255; M-1 to F-254; M-1 toY-253; M-1 to P-252; M-1 to T-251; M-1 to L-250; M-1 to Q-249; M-1 toV-248; M-1 to T-247; M-1 to A-246; M-1 to G-245; M-1 to E-244; M-1 toS-243; M-1 to D-242; M-1 to G-241; M-1 to T-240; M-1 to V-239; M-1 toP-238; M-1 to I-237; M-1 to V-236; M-1 to V-235; M-1 to S-234; M-1 toA-233; M-1 to R-232; M-1 to T-231; M-1 to Q-230; M-1 to K-229; M-1 toK-228; M-1 to Q-227; M-1 to H-226; M-1 to P-225; M-1 to E-224; M-1 toF-223; M-1 to V-222; M-1 to Q-221; M-1 to S-220; M-1 to F-219; M-1 toG-218; M-1 to I-217; M-1 to I-216; M-1 to T-215; M-1 to S-214; M-1 toH-213; M-1 to Q-212; M-1 to I-211; M-1 to L-210; M-1 to A-209; M-1 toM-208; M-1 to Y-207; M-1 to R-206; M-1 to N-205; M-1 to G-204; M-1 toL-203; M-1 to P-202; M-1 to T-201; M-1 to T-200; M-1 to T-199; M-1 toF-198; M-1 to N-197; M-1 to V-196; M-1 to E-195; M-1 to V-194; M-1 toT-193; M-1 to E-192; M-1 to E-191; M-1 to N-190; M-1 to K-189; M-1 toK-188; M-1 to C-187; M-1 to A-186; M-1 to T-185; M-1 to I-184; M-1 toN-183; M-1 to P-182; M-1 to D-181; M-1 to W-180; M-1 to L-179; M-1 toS-178; M-1 to G-177; M-1 to A-176; M-1 to K-175; M-1 to V-174; M-1 toC-173; M-1 to K-172; M-1 to K-171; M-1 to K-170; M-1 to Y-169; M-1 toK-168; M-1 to M-167; M-1 to I-166; M-1 to H-165; M-1 to D-164; M-1 toL-163; M-1 to C-162; M-1 to G-161; M-1 to P-160; M-1 to S-159; M-1 toT-158; M-1 to F-157; M-1 to N-156; M-1 to V-155; M-1 to S-154; M-1 toM-153; M-1 to S-152; M-1 to P-151; M-1 to G-150; M-1 to D-149; M-1 toE-148; M-1 to N-147; M-1 to M-146; M-1 to N-145; M-1 to A-144; M-1 toN-143; M-1 to P-142; M-1 to I-141; M-1 to N-140; M-1 to H-139; M-1 toA-138; M-1 to G-137; M-1 to I-136; M-1 to F-135; M-1 to Y-134; M-1 toV-133; M-1 to T-132; M-1 to N-131; M-1 to L-130; M-1 to E-129; M-1 toV-128; M-1 to P-127; M-1 to F-126; M-1 to G-125; M-1 to I-124; M-1 toY-123; M-1 to S-122; M-1 to F-121; M-1 to T-120; M-1 to W-119; M-1 toK-118; M-1 to G-117; M-1 to G-116; M-1 to S-115; M-1 to P-114; M-1 toR-113; M-1 to T-112; M-1 to Q-111; M-1 to T-110; M-1 to Q-109; M-1 toF-108; M-1 to A-107; M-1 to E-106; M-1 to T-105; M-1 to Y-104; M-1 toN-103; M-1 to C-102; M-1 to R-101; M-1 to V-100; M-1 to C-99; M-1 toS-98; M-1 to Y-97; M-1 to S-96; M-1 to Q-95; M-1 to F-94; M-1 to N-93;M-1 to S-92; M-1 to K-91; M-1 to G-90; M-1 to T-89; M-1 to V-88; M-1 toC-87; M-1 to I-86; M-1 to K-85; M-1 to T-84; M-1 to A-83; M-1 to K-82;M-1 to L-81; M-1 to L-80; M-1 to R-79; M-1 to I-78; M-1 to S-77; M-1 toA-76; M-1 to D-75; M-1 to A-74; M-1 to R-73; M-1 to L-72; M-1 to V-71;M-1 to W-70; M-1 to S-69; M-1 to V-68; M-1 to N-67; M-1 to M-66; M-1 toL-65; M-1 to I-64; M-1 to S-63; M-1 to Y-62; M-1 to D-61; M-1 to G-60;M-1 to T-59; M-1 to A-58; M-1 to V-57; M-1 to S-56; M-1 to T-55; M-1 toT-54; M-1 to V-53; M-1 to P-52; M-1 to E-51; M-1 to V-50; M-1 to R-49;M-1 to L-48; M-1 to D-47; M-1 to R-46; M-1 to L-45; M-1 to D-44; M-1 toG-43; M-1 to P-42; M-1 to I-41; M-1 to L-40; M-1 to D-39; M-1 to H-38;M-1 to Q-37; M-1 to L-36; M-1 to M-35; M-1 to W-34; M-1 to E-33; M-1 toP-32; M-1 to S-31; M-1 to P-30; M-1 to G-29; M-1 to T-28; M-1 to E-27;M-1 to S-26; M-1 to G-25; M-1 to C-24; M-1 to Q-23; M-1 to V-22; M-1 toT-21; M-1 to P-20; M-1 to E-19; M-1 to R-18; M-1 to P-17; M-1 to V-16;M-1 to A-15; M-1 to S-14; M-1 to R-13; M-1 to C-12; M-1 to L-11; M-1 toA-10; M-1 to A-9; M-1 to L-8; M-1 to S-7; and M-1 to L-6 of the sequenceof the IL17RLP sequence shown in FIGS. 1A, 1B, and 1C (which isidentical to the sequence shown as SEQ ID NO:2, with the exception thatthe amino acid residues in FIGS. 1A, 1B, and 1C are numberedconsecutively from 1 through 426 from the N-terminus to the C-terminus,while the amino acid residues in SEQ ID NO:2 are numbered consecutivelyfrom −19 through 406 to reflect the position of the predicted signalpeptide). Polynucleotides encoding these polypeptides also are provided.

[0126] The invention also provides polypeptides having one or more aminoacids deleted from both the amino and the carboxyl termini of an IL17RLPpolypeptide, which may be described generally as having residues n²-m²of FIGS. 1A, 1B, and 1C (SEQ ID NO:2), where n² and m² are integers asdescribed above.

[0127] Other Mutants

[0128] In addition to terminal deletion forms of the protein discussedabove, it also will be recognized by one of ordinary skill in the artthat some amino acid sequences of the IL17RLP polypeptide can be variedwithout significant effect of the structure or function of the protein.If such differences in sequence are contemplated, it should beremembered that there will be critical areas on the protein whichdetermine activity.

[0129] Thus, the invention further includes variations of the IL17RLPpolypeptide which show substantial IL17RLP polypeptide activity or whichinclude regions of IL17RLP protein such as the protein portionsdiscussed below. Such mutants include deletions, insertions, inversions,repeats, and type substitutions selected according to general rulesknown in the art so as have little effect on activity. For example,guidance concerning how to make phenotypically silent amino acidsubstitutions is provided wherein the authors indicate that there aretwo main approaches for studying the tolerance of an amino acid sequenceto change (Bowie, J. U., et al., Science 247:1306-1310 (1990)),. Thefirst method relies on the process of evolution, in which mutations areeither accepted or rejected by natural selection. The second approachuses genetic engineering to introduce amino acid changes at specificpositions of a cloned gene and selections or screens to identifysequences that maintain functionality.

[0130] As the authors state, these studies have revealed that proteinsare surprisingly tolerant of amino acid substitutions. The authorsfurther indicate which amino acid changes are likely to be permissive ata certain position of the protein. For example, most buried amino acidresidues require nonpolar side chains, whereas few features of surfaceside chains are generally conserved. Other such phenotypically silentsubstitutions are described by Bowie and coworkers (supra) and thereferences cited therein. Typically seen as conservative substitutionsare the replacements, one for another, among the aliphatic amino acidsAla, Val, Leu and Ile; interchange of the hydroxyl residues Ser and Thr,exchange of the acidic residues Asp and Glu, substitution between theamide residues Asn and Gln, exchange of the basic residues Lys and Argand replacements among the aromatic residues Phe, Tyr.

[0131] Thus, the fragment, derivative or analog of the polypeptide ofSEQ ID NO:2, or that encoded by the deposited cDNA, may be (i) one inwhich one or more of the amino acid residues are substituted with aconserved or non-conserved amino acid residue (preferably a conservedamino acid residue) and such substituted amino acid residue may or maynot be one encoded by the genetic code, or (ii) one in which one or moreof the amino acid residues includes a substituent group, or (iii) one inwhich the mature polypeptide is fused with another compound, such as acompound to increase the half-life of the polypeptide (for example,polyethylene glycol), or (iv) one in which the extracellular domain ofthe polypeptide is fused with another compound, such as a compound toincrease the half-life of the polypeptide (for example, polyethyleneglycol), or (v) one in which the additional amino acids are fused to theabove form of the polypeptide, such as an IgG Fc fusion region peptideor leader or secretory sequence or a sequence which is employed forpurification of the above form of the polypeptide or a proproteinsequence. Such fragments, derivatives and analogs are deemed to bewithin the scope of those skilled in the art from the teachings herein.

[0132] Thus, the IL17RLP of the present invention may include one ormore amino acid substitutions, deletions or additions, either fromnatural mutations or human manipulation. As indicated, changes arepreferably of a minor nature, such as conservative amino acidsubstitutions that do not significantly affect the folding or activityof the protein (see Table II). TABLE II Conservative Amino AcidSubstitutions. Aromatic Phenylalanine Tryptophan Tyrosine HydrophobicLeucine Isoleucine Valine Polar Glutamine Asparagine Basic ArginineLysine Histidine Acidic Aspartic Acid Glutamic Acid Small Alanine SerineThreonine Methionine Glycine

[0133] Embodiments of the invention are directed to polypeptides whichcomprise the amino acid sequence of an IL17RLP polypeptide descrubedhereub, but having an amino acid sequence which contains at least oneconservative amino acid substitution, but not more than 50 conservativeamino acid substitutions, even more preferably, not more than 40conservative amino acid substitutions, still more preferably, not morethan 30 conservative amino acid substitutions, and still even morepreferably, not more than 20 conservative amino acid substitutions, whencompared with the follistatin-3 polynucleotide sequence describedherein. Of course, in order of ever-increasing preference, it is highlypreferable for a peptide or polypeptide to have an amino acid sequencewhich comprises the amino acid sequence of an IL17RLP polypeptide, whichcontains at least one, but not more than 20, 10, 9, 8, 7, 6, 5, 4, 3, 2or 1 conservative amino acid substitutions.

[0134] In further specific embodiments, the number of substitutions,additions or deletions in the amino acid sequence of FIGS. 1A, 1B, and1C (SEQ ID NO:2), a polypeptide sequence encoded by the depositedclones, and/or any of the polypeptide fragments described herein is 150,100, 75, 70, 60, 50, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2,1 or 250-150, 200-50, 150-50, 100-50, 50-20, 30-20, 20-15, 20-10, 15-10,10-1, 5-10, 1-5, 1-3 or 1-2.

[0135] To improve or alter the characteristics of IL17RLP polypeptides,protein engineering may be employed. Recombinant DNA technology known tothose skilled in the art can be used to create novel mutant proteins ormuteins including single or multiple amino acid substitutions,deletions, additions or fusion proteins. Such modified polypeptides canshow, e.g., enhanced activity or increased stability. In addition, theymay be purified in higher yields and show better solubility than thecorresponding natural polypeptide, at least under certain purificationand storage conditions.

[0136] Thus, the invention also encompasses IL17RLP derivatives andanalogs that have one or more amino acid residues deleted, added, orsubstituted to generate IL17RLP polypeptides that are better suited forexpression, scale up, etc., in the host cells chosen. For example,cysteine residues can be deleted or substituted with another amino acidresidue in order to eliminate disulfide bridges, PKC phosphorylationsites, CK2 phosphorylation sites, cAMP- and cGMP-dependent proteinkinase phosphorylation sites, myristolation, and/or N-linkedglycosylation sites can be altered or eliminated to acheive an alterredfunction or expression pattern of the polypeptide (for example, amutated N-linked glycosylation site may alter the expression of ahomogeneous product that is more easily recovered and purified fromyeast hosts which are known to hyperglycosylate N-linked sites). To thisend, a variety of amino acid substitutions at one or both of the firstor third amino acid positions on any one or more of the disulfide bridgecysteines, PKC phosphorylation sites, CK2 phosphorylation sites, cAMP-and cGMP-dependent protein kinase phosphorylation sites, myristolation,and/or glycosylation recognition sequences in the IL17RLP polypeptidesof the invention, and/or an amino acid deletion at the second positionof any one or more such recognition sequences will alter function orexpression or prevent glycosylation of the IL17RLP polypeptide at themodified tripeptide sequence (see, e.g., Miyajima, A., et al., EMBO J.5(6):1193-1197 (1986)).

[0137] Amino acids in the IL17RLP protein of the present invention thatare essential for function can be identified by methods known in theart, such as site-directed mutagenesis or alanine-scanning mutagenesis(Cunningham and Wells, Science 244:1081-1085 (1989)). The latterprocedure introduces single alanine mutations at every residue in themolecule. The resulting mutant molecules are then tested for biologicalactivity such as receptor binding or in vitro proliferative activity.

[0138] Of special interest are substitutions of charged amino acids withother charged or neutral amino acids which may produce proteins withhighly desirable improved characteristics, such as less aggregation.Aggregation may not only reduce activity but also be problematic whenpreparing pharmaceutical formulations, because aggregates can beimmunogenic (Pinckard, et al., Clin. Exp. Immunol. 2:331-340 (1967);Robbins, et al., Diabetes 36:838-845 (1987); Cleland, et al., Crit. Rev.Therapeutic Drug Carrier Systems 10:307-377 (1993)).

[0139] Replacement of amino acids can also change the selectivity of thebinding of a ligand to cell surface receptors (for example, Ostade, etal., Nature 361:266-268 (1993)) describes certain mutations resulting inselective binding of TNF-α to only one of the two known types of TNFreceptors. Sites that are critical for ligand-receptor binding can alsobe determined by structural analysis such as crystallization, nuclearmagnetic resonance or photoaffinity labeling (Smith, et al., J. Mol.Biol. 224:899-904 (1992); de Vos, et al. Science 255:306-312 (1992)).

[0140] Since IL17RLP is a homologue of the murine IL-17 receptorprotein, to modulate rather than completely eliminate biologicalactivities of IL17RLP preferably mutations are made in sequencesencoding amino acids in the IL17RLP conserved extracellular domain,i.e., in positions 1-271 of SEQ ID NO:2, more preferably in residueswithin this region which are not conserved in the murine IL-17 receptorprotein. Also forming part of the present invention are isolatedpolynucleotides comprising nucleic acid sequences which encode the aboveIL17RLP mutants.

[0141] Amino acid regions of the IL17RLP sequence shown in SEQ ID NO:2which are highly conserved when compared to the murine IL-17Rpolypeptide sequence shown as SEQ ID NO:3 (see FIG. 2) are attractiveregions for targeted mutagenesis of the IL17RLP polypeptides of theinvention. In fact, a number of conserved regions or domains have beenset forth in FIGS. 1A, 1B, and 1C (labeled as Domains I-VIII). Thesedomains are as follows: Domain I (i.e., Val-49 through Leu-62 of SEQ IDNO:2 (Val-68 through Leu-81 of FIGS. 1A, 1B, and 1C)); Domain II(Cys-154 through Thr-166 of SEQ ID NO:2 (i.e., Cys-173 through Thr-185of FIGS. 1A, 1B, and 1C)); Domain III (Gln-202 through Gln-208 of SEQ IDNO:2 (i.e., Gln-221 through Gln-227 of FIGS. 1A, 1B, and 1C)); Domain IV(Asp-241 through Val-249 of SEQ ID NO:2 (i.e., Asp-260 through Val-268of FIGS. 1A, 1B, and 1C)); Domain V (Thr-255 through Leu-261 of SEQ IDNO:2 (i.e., Thr-274 through Leu-280 of FIGS. 1A, 1B, and 1C)); Domain VI(Leu-310 through Tyr-319 of SEQ ID NO:2 (i.e., Leu-329 through Tyr-338of FIGS. 1A, 1B, and 1C)); Domain VII (Cys-340 through Leu-346 of SEQ IDNO:2 (i.e., Cys-359 through Leu-365 of FIGS. 1A, 1B, and 1C)); andDomain VII (Ile-354 through Gly-358 of SEQ ID NO:2 (i.e., Ile-373through Gly-377 of FIGS. 1A, 1B, and 1C)).

[0142] In another embodiment of the invention, seven cysteine residuesof IL17RLP are conserved with respect to the murine IL-17R polypeptidesequence shown in SEQ ID NO:3. Cysteine residues tend to play animportant role in the structural conformation, and thus, the function ofa polypeptide. As such, the seven conserved cysteine residues are alsoattractive residues for targeted mutagenesis of the IL17RLP polypeptidesof the invention. The seven highly conserved cysteine residues of theIL17RLP shown in SEQ ID NO:2 of the present invention are as follows:Cys-5, Cys-80, Cys-143, Cys-154, Cys-238, Cys-242, and Cys-340 of SEQ IDNO:2 (which correspond exactly to Cys-24, Cys-99, Cys-162, Cys-173,Cys-257, Cys-261, and Cys-359 of FIGS. 1A, 1B, and 1C).

[0143] The polypeptides of the present invention are preferably providedin an isolated form, and preferably are substantially purified. Arecombinantly produced version of the IL17RLP polypeptide can besubstantially purified by the one-step method described by Smith andJohnson (Gene 67:31-40 (1988)). Polypeptides of the invention also canbe purified from natural or recombinant sources using anti-IL17RLPantibodies of the invention in methods which are well known in the artof protein purification.

[0144] The invention further provides an isolated IL17RLP polypeptidecomprising an amino acid sequence selected from the group consisting of:(a) the amino acid sequence of the full-length IL17RLP polypeptidehaving the complete amino acid sequence shown in SEQ ID NO:2 (i.e.,positions −19 to 407 of SEQ ID NO:2); (b) the amino acid sequence of thefull-length IL17RLP polypeptide having the complete amino acid sequenceshown in SEQ ID NO:2 excepting the N-terminal methionine (i.e.,positions −18 to 407 of SEQ ID NO:2); (c) the amino acid sequence of themature IL17RLP polypeptide having the complete amino acid sequence shownin SEQ ID NO:2 (i.e., positions 1 to 407 of SEQ ID NO:2); (d) the aminoacid sequence of the predicted extracellular domain of the IL17RLPpolypeptide having the complete amino acid sequence shown in SEQ ID NO:2(i.e., positions 1 to 271 of SEQ ID NO:2); (e) the amino acid sequenceof a soluble IL17RLP polypeptide having the predicted extracellular andintracellular domains, but lacking the predicted transmembrane domain;(f) the complete amino acid sequence encoded by the human cDNA containedin the ATCC Deposit No. 209198; (g) the complete amino acid sequenceexcepting the N-terminal methionine encoded by the human cDNA containedin the ATCC Deposit No. 209198; (h) the complete amino acid sequence ofthe mature IL17RLP encoded by the human cDNA contained in the ATCCDeposit No. 209198, and; (i) the complete amino acid sequence of theextracellular domain of the IL17RLP encoded by the human cDNA containedin the ATCC Deposit No. 209198. The polypeptides of the presentinvention also include polypeptides having an amino acid sequence atleast 80% identical, more preferably at least 90% identical, and stillmore preferably 95%, 96%, 97%, 98% or 99% identical to those describedin (a), (b), (c), (d), (e), (f), (g), (h) or (i) above, as well aspolypeptides having an amino acid sequence with at least 90% similarity,and more preferably at least 95% similarity, to those above.

[0145] Further polypeptides of the present invention includepolypeptides which have at least 90% similarity, more preferably atleast 95% similarity, and still more preferably at least 96%, 97%, 98%or 99% similarity to those described above. The polypeptides of theinvention also comprise those which are at least 80% identical, morepreferably at least 90% or 95% identical, still more preferably at least96%, 97%, 98% or 99% identical to the polypeptide encoded by thedeposited cDNA or to the polypeptide of SEQ ID NO:2, and also includeportions of such polypeptides with at least 30 amino acids and morepreferably at least 50 amino acids.

[0146] By “% similarity” for two polypeptides is intended a similarityscore produced by comparing the amino acid sequences of the twopolypeptides using the Bestfit program (Wisconsin Sequence AnalysisPackage, Version 8 for Unix, Genetics Computer Group, UniversityResearch Park, 575 Science Drive, Madison, Wis. 53711) and the defaultsettings for determining similarity. Bestfit uses the local homologyalgorithm of Smith and Waterman (Advances in Applied Mathematics2:482-489, 1981) to find the best segment of similarity between twosequences.

[0147] By a polypeptide having an amino acid sequence at least, forexample, 95% “identical” to a reference amino acid sequence of a IL17RLPpolypeptide is intended that the amino acid sequence of the polypeptideis identical to the reference sequence except that the polypeptidesequence may include up to five amino acid alterations per each 100amino acids of the reference amino acid of the IL17RLP polypeptide. Inother words, to obtain a polypeptide having an amino acid sequence atleast 95% identical to a reference amino acid sequence, up to 5% of theamino acid residues in the reference sequence may be deleted orsubstituted with another amino acid, or a number of amino acids up to 5%of the total amino acid residues in the reference sequence may beinserted into the reference sequence. These alterations of the referencesequence may occur at the amino or carboxy terminal positions of thereference amino acid sequence or anywhere between those terminalpositions, interspersed either individually among residues in thereference sequence or in one or more contiguous groups within thereference sequence.

[0148] As a practical matter, whether any particular polypeptide is atleast 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, theamino acid sequence shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:2), theamino acid sequence encoded by deposited cDNA clone HAPOR40, orfragments thereof, can be determined conventionally using known computerprograms such the Bestfit program (Wisconsin Sequence Analysis Package,Version 8 for Unix, Genetics Computer Group, University Research Park,575 Science Drive, Madison, Wis. 53711). When using Bestfit or any othersequence alignment program to determine whether a particular sequenceis, for instance, 95% identical to a reference sequence according to thepresent invention, the parameters are set, of course, such that thepercentage of identity is calculated over the full length of thereference amino acid sequence and that gaps in homology of up to 5% ofthe total number of amino acid residues in the reference sequence areallowed.

[0149] In a specific embodiment, the identity between a reference(query) sequence (a sequence of the present invention) and a subjectsequence, also referred to as a global sequence alignment, is determinedusing the FASTDB computer program based on the algorithm of Brutlag etal. (Comp. App. Biosci. 6:237-245 (1990)). Preferred parameters used ina FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, MismatchPenalty=1, Joining Penalty=20, Randomization Group Length=0, CutoffScore=1, Window Size=sequence length, Gap Penalty=5, Gap SizePenalty=0.05, Window Size=500 or the length of the subject amino acidsequence, whichever is shorter. According to this embodiment, if thesubject sequence is shorter than the query sequence due to N- orC-terminal deletions, not because of internal deletions, a manualcorrection is made to the results to take into consideration the factthat the FASTDB program does not account for N- and C-terminaltruncations of the subject sequence when calculating global percentidentity. For subject sequences truncated at the N- and C-termini,relative to the query sequence, the percent identity is corrected bycalculating the number of residues of the query sequence that are N- andC-terminal of the subject sequence, which are not matched/aligned with acorresponding subject residue, as a percent of the total bases of thequery sequence. A determination of whether a residue is matched/alignedis determined by results of the FASTDB sequence alignment. Thispercentage is then subtracted from the percent identity, calculated bythe above FASTDB program using the specified parameters, to arrive at afinal percent identity score. This final percent identity score is whatis used for the purposes of this embodiment. Only residues to the N- andC-termini of the subject sequence, which are not matched/aligned withthe query sequence, are considered for the purposes of manuallyadjusting the percent identity score. That is, only query residuepositions outside the farthest N- and C-terminal residues of the subjectsequence. For example, a 90 amino acid residue subject sequence isaligned with a 100 residue query sequence to determine percent identity.The deletion occurs at the N-terminus of the subject sequence andtherefore, the FASTDB alignment does not show a matching/alignment ofthe first 10 residues at the N-terminus. The 10 unpaired residuesrepresent 10% of the sequence (number of residues at the N- andC-termini not matched/total number of residues in the query sequence) so10% is subtracted from the percent identity score calculated by theFASTDB program. If the remaining 90 residues were perfectly matched thefinal percent identity would be 90%. In another example, a 90 residuesubject sequence is compared with a 100 residue query sequence. Thistime the deletions are internal deletions so there are no residues atthe N- or C-termini of the subject sequence which are notmatched/aligned with the query. In this case the percent identitycalculated by FASTDB is not manually corrected. Once again, only residuepositions outside the N- and C-terminal ends of the subject sequence, asdisplayed in the FASTDB alignment, which are not matched/aligned withthe query sequence are manually corrected for. No other manualcorrections are made for the purposes of this embodiment.

[0150] The invention also encompasses fusion proteins in which thefull-length IL17RLP polypeptide or fragment, variant, derivative, oranalog thereof is fused or joined to an unrelated protein. These fusionproteins can be routinely designed on the basis of the IL17RLPnucleotide and polypeptide sequences disclosed herein. For example, asone of skill in the art will appreciate, IL17RLP polypeptides andfragments (including epitope-bearing fragments) thereof described hereincan be combined with parts of the constant domain of immunoglobulins(IgG), resulting in chimeric (fusion) polypeptides. These fusionproteins facilitate purification and show an increased half-life invivo. This has been shown, e.g., for chimeric proteins consisting of thefirst two domains of the human CD4-polypeptide and various domains ofthe constant regions of the heavy or light chains of mammalianimmunoglobulins (EP A 394,827; Traunecker, et aL, Nature 331:84-86(1988)). Fusion proteins that have a disulfide-linked dimeric structuredue to the IgG part can also be more efficient in binding andneutralizing other molecules than the monomeric IL17RLP polypeptide orpolypeptide fragments alone (Fountoulakis, et al., J. Biochem.270:3958-3964 (1995)). Examples of IL17RLP fusion proteins that areencompassed by the invention include, but are not limited to, fusion ofthe IL17RLP polypeptide sequences to any amino acid sequence that allowsthe fusion proteins to be displayed on the cell surface (e.g. the IgG Fcdomain); or fusions to an enzyme, fluorescent protein, or luminescentprotein which provides a marker function.

[0151] As described in detail below, the polypeptides of the presentinvention can also be used to raise polyclonal and monoclonalantibodies, which are useful in assays for detecting IL17RLP proteinexpression as described below or as agonists and antagonists capable ofenhancing or inhibiting IL17RLP protein function. Further, suchpolypeptides can be used in the yeast two-hybrid system to “capture”IL17RLP protein binding proteins which are also candidate agonists andantagonists according to the present invention. The yeast two hybridsystem is described by Fields and Song (Nature 340:245-246 (1989)).

[0152] Epitope-Bearing Portions

[0153] In another aspect, the invention provides a peptide orpolypeptide comprising an epitope-bearing portion of a polypeptide ofthe invention. The epitope of this polypeptide portion is an immunogenicor antigenic epitope of a polypeptide of the invention. An “immunogenicepitope” is defined as a part of a protein that elicits an antibodyresponse when the whole protein is the immunogen. On the other hand, aregion of a protein molecule to which an antibody can bind is defined asan “antigenic epitope.” The number of immunogenic epitopes of a proteingenerally is less than the number of antigenic epitopes (see, forinstance, Geysen, et al., Proc. Natl. Acad. Sci. USA 81:3998-4002(1983)).

[0154] As to the selection of peptides or polypeptides bearing anantigenic epitope (i.e., that contain a region of a protein molecule towhich an antibody can bind), it is well known in that art thatrelatively short synthetic peptides that mimic part of a proteinsequence are routinely capable of eliciting an antiserum that reactswith the partially mimicked protein (see, for instance, Sutcliffe, J.G., et al., Science 219:660-666 (1983)). Peptides capable of elicitingprotein-reactive sera are frequently represented in the primary sequenceof a protein, can be characterized by a set of simple chemical rules,and are confined neither to immunodominant regions of intact proteins(i.e., immunogenic epitopes) nor to the amino or carboxyl terminals.Antigenic epitope-bearing peptides and polypeptides of the invention aretherefore useful to raise antibodies, including monoclonal antibodies,that bind specifically to a polypeptide of the invention (see, forinstance, Wilson, et al., Cell 37:767-778 (1984)).

[0155] Antigenic epitope-bearing peptides and polypeptides of theinvention preferably contain a sequence of at least seven, morepreferably at least nine and most preferably between about 15 to about30 amino acids contained within the amino acid sequence of a polypeptideof the invention. Non-limiting examples of antigenic polypeptides orpeptides that can be used to generate IL17RLP-specific antibodiesinclude: a polypeptide comprising amino acid residues from about Ser-14to about Val-22 in SEQ ID NO:2, a polypeptide comprising amino acidresidues from about Cys-24 to about Pro-32 in SEQ ID NO:2, a polypeptidecomprising amino acid residues from about Ile-41 to about Arg-49 in SEQID NO:2, a polypeptide comprising amino acid residues from about Thr-89to about Val-97 in SEQ ID NO:2, a polypeptide comprising amino acidresidues from about Thr-110 to about Lys-118 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Ala-144 to aboutSer-152 in SEQ ID NO:2, a polypeptide comprising amino acid residuesfrom about Thr-240 to about Val-248 in SEQ ID NO:2, a polypeptidecomprising amino acid residues from about Gly-258 to about Thr-267 inSEQ ID NO:2, a polypeptide comprising amino acid residues from aboutLeu-280 to about Gly-288 in SEQ ID NO:2, a polypeptide comprising aminoacid residues from about Cys-404 to about Glu-412 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Pro-415 to aboutSer-423 in SEQ ID NO:2, a polypeptide comprising amino acid residuesfrom about Gly-409 to about Glu-417 in SEQ ID NO:2, and a polypeptidecomprising amino acid residues from about Cys-404 to about Leu-426 inFIGS. 1A, 1B, and 1C (which is identical to the sequence shown in SEQ IDNO:2 with the exception of the numbering scheme as detailed above).These polypeptide fragments have been determined to bear antigenicepitopes of the IL17RLP protein by the analysis of the Jameson-Wolfantigenic index, as shown in FIG. 3, above.

[0156] The epitope-bearing peptides and polypeptides of the inventionmay be produced by any conventional means (see, for example, Houghten,R. A., et al., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985); and U.S.Pat. No. 4,631,211 to Houghten, et al. (1986)).

[0157] Epitope-bearing peptides and polypeptides of the invention areused to induce antibodies according to methods well known in the art(see, for instance, Sutcliffe, et al., supra; Wilson, et al., supra;Chow, M., et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle, F.J., et al., J. Gen. Virol. 66:2347-2354 (1985)). Immunogenicepitope-bearing peptides of the invention, i.e., those parts of aprotein that elicit an antibody response when the whole protein is theimmunogen, are identified according to methods known in the art (see,for instance, Geysen, et al., supra). Further still, U.S. Pat. No.5,194,392, issued to Geysen, describes a general method of detecting ordetermining the sequence of monomers (amino acids or other compounds)which is a topological equivalent of the epitope (i.e., a “mimotope”)which is complementary to a particular paratope (antigen binding site)of an antibody of interest. More generally, U.S. Pat. No. 4,433,092,issued to Geysen, describes a method of detecting or determining asequence of monomers which is a topographical equivalent of a ligandwhich is complementary to the ligand binding site of a particularreceptor of interest. Similarly, U.S. Pat. No. 5,480,971, issued toHoughten and colleagues, on Peralkylated Oligopeptide Mixtures discloseslinear C1-C7-alkyl peralkylated oligopeptides and sets and libraries ofsuch peptides, as well as methods for using such oligopeptide sets andlibraries for determining the sequence of a peralkylated oligopeptidethat preferentially binds to an acceptor molecule of interest. Thus,non-peptide analogs of the epitope-bearing peptides of the inventionalso can be made routinely by these methods.

[0158] Fusion Proteins

[0159] As one of skill in the art will appreciate, IL17RLP polypeptidesof the present invention and the epitope-bearing fragments thereofdescribed above can be combined with parts of the constant domain ofimmunoglobulins (IgG), resulting in chimeric polypeptides. These fusionproteins facilitate purification and show an increased half-life invivo. This has been shown, e.g., for chimeric proteins consisting of thefirst two domains of the human CD4-polypeptide and various domains ofthe constant regions of the heavy or light chains of mammalianimmunoglobulins (EP A 394,827; Traunecker, et al., Nature 331:84-86(1988)). Fusion proteins that have a disulfide-linked dimeric structuredue to the IgG part can also be more efficient in binding andneutralizing other molecules than the monomeric IL17RLP protein orprotein fragment alone (Fountoulakis, et al., J. Biochem. 270:3958-3964(1995)).

[0160] Antibodies

[0161] IL17RLP protein-specific antibodies for use in the presentinvention can be raised against the intact IL17RLP protein or anantigenic polypeptide fragment thereof, which may be presented togetherwith a carrier protein, such as an albumin, to an animal system (such asrabbit or mouse) or, if it is long enough (at least about 25 aminoacids), without a carrier.

[0162] As used herein, the term “antibody” (Ab) or “monoclonal antibody”(Mab) is meant to include intact molecules as well as antibody fragments(such as, for example, Fab and F(ab′)2 fragments) which are capable ofspecifically binding to IL17RLP protein. Fab and F(ab′)2 fragments lackthe Fc fragment of intact antibody, clear more rapidly from thecirculation, and may have less non-specific tissue binding of an intactantibody (Wahl, et al., J. Nucl. Med. 24:316-325 (1983)). Thus, thesefragments are preferred.

[0163] The antibodies of the present invention may be prepared by any ofa variety of methods. For example, cells expressing the IL17RLP proteinor an antigenic fragment thereof can be administered to an animal inorder to induce the production of sera containing polyclonal antibodies.In a preferred method, a preparation of IL17RLP protein is prepared andpurified to render it substantially free of natural contaminants. Such apreparation is then introduced into an animal in order to producepolyclonal antisera of greater specific activity.

[0164] In the most preferred method, the antibodies of the presentinvention are monoclonal antibodies (or IL17RLP protein bindingfragments thereof). Such monoclonal antibodies can be prepared usinghybridoma technology (Kohler, et al., Nature 256:495 (1975); Kohler, etal., Eur. J. Immunol. 6:511 (1976); Kohler, et al., Eur. J. Immunol.6:292 (1976); Hammerling, et al., in: Monoclonal Antibodies and T-CellHybridomas, Elsevier, N.Y., (1981) pp. 563-681)). In general, suchprocedures involve immunizing an animal (preferably a mouse) with aIL17RLP protein antigen or, more preferably, with a IL17RLPprotein-expressing cell. Suitable cells can be recognized by theircapacity to bind anti-IL17RLP protein antibody. Such cells may becultured in any suitable tissue culture medium; however, it ispreferable to culture cells in Earle's modified Eagle's mediumsupplemented with 10% fetal bovine serum (inactivated at about 56° C.),and supplemented with about 10 μg/l of nonessential amino acids, about1,000 U/ml of penicillin, and about 100 μg/ml of streptomycin. Thesplenocytes of such mice are extracted and fused with a suitable myelomacell line. Any suitable myeloma cell line may be employed in accordancewith the present invention; however, it is preferable to employ theparent myeloma cell line (SP2O), available from the American TypeCulture Collection, Manassas, Va. After fusion, the resulting hybridomacells are selectively maintained in HAT medium, and then cloned bylimiting dilution as described by Wands and colleagues (Gastroenterology80:225-232 (1981)). The hybridoma cells obtained through such aselection are then assayed to identify clones which secrete antibodiescapable of binding the IL17RLP protein antigen.

[0165] Alternatively, additional antibodies capable of binding to theIL17RLP protein antigen may be produced in a two-step procedure throughthe use of anti-idiotypic antibodies. Such a method makes use of thefact that antibodies are themselves antigens, and that, therefore, it ispossible to obtain an antibody which binds to a second antibody. Inaccordance with this method, IL17RLP protein-specific antibodies areused to immunize an animal, preferably a mouse. The splenocytes of suchan animal are then used to produce hybridoma cells, and the hybridomacells are screened to identify clones which produce an antibody whoseability to bind to the IL17RLP protein-specific antibody can be blockedby the IL17RLP protein antigen. Such antibodies comprise anti-idiotypicantibodies to the IL17RLP protein-specific antibody and can be used toimmunize an animal to induce formation of further IL17RLPprotein-specific antibodies.

[0166] It will be appreciated that Fab and F(ab′)2 and other fragmentsof the antibodies of the present invention may be used according to themethods disclosed herein. Such fragments are typically produced byproteolytic cleavage, using enzymes such as papain (to produce Fabfragments) or pepsin (to produce F(ab′)2 fragments). Alternatively,IL17RLP protein-binding fragments can be produced through theapplication of recombinant DNA technology or through syntheticchemistry.

[0167] For in vivo use of anti-IL17RLP in humans, it may be preferableto use “humanized” chimeric monoclonal antibodies. Such antibodies canbe produced using genetic constructs derived from hybridoma cellsproducing the monoclonal antibodies described above. Methods forproducing chimeric antibodies are known in the art (Morrison, Science229:1202 (1985); Oi, et al., BioTechniques 4:214 (1986); Cabilly, etal., U.S. Pat. No. 4,816,567; Taniguchi, et al., EP 171496; Morrison, etal., EP 173494; Neuberger, et al., WO 8601533; Robinson, et al., WO8702671; Boulianne, et al., Nature 312:643 (1984); Neuberger, et al.,Nature 314:268 (1985).

Immune System-Related Disorders

[0168] Diagnosis

[0169] The present inventors have discovered that IL17RLP is expressedin adult pulmonary tissue. For a number of immune system-relateddisorders, substantially altered (increased or decreased) levels ofIL17RLP gene expression can be detected in immune system tissue or othercells or bodily fluids (e.g., sera, plasma, urine, synovial fluid orspinal fluid) taken from an individual having such a disorder, relativeto a “standard” IL17RLP gene expression level, that is, the IL17RLPexpression level in immune system tissues or bodily fluids from anindividual not having the immune system disorder. Thus, the inventionprovides a diagnostic method useful during diagnosis of an immune systemdisorder, which involves measuring the expression level of the geneencoding the IL17RLP protein in immune system tissue or other cells orbody fluid from an individual and comparing the measured gene expressionlevel with a standard IL17RLP gene expression level, whereby an increaseor decrease in the gene expression level compared to the standard isindicative of an immune system disorder.

[0170] In particular, it is believed that certain tissues in mammalswith cancer of the immune system express significantly enhanced levelsof the IL17RLP protein and mRNA encoding the IL17RLP protein whencompared to a corresponding “standard” level. Further, it is believedthat enhanced levels of the IL17RLP protein can be detected in certainbody fluids (e.g., sera, plasma, urine, and spinal fluid) from mammalswith such a cancer when compared to sera from mammals of the samespecies not having the cancer.

[0171] Thus, the invention provides a diagnostic method useful duringdiagnosis of an immune system disorder, including cancers of thissystem, which involves measuring the expression level of the geneencoding the IL17RLP protein in immune system tissue or other cells orbody fluid from an individual and comparing the measured gene expressionlevel with a standard IL17RLP gene expression level, whereby an increaseor decrease in the gene expression level compared to the standard isindicative of an immune system disorder.

[0172] Where a diagnosis of a disorder in the immune system includingdiagnosis of a tumor, has already been made according to conventionalmethods, the present invention is useful as a prognostic indicator,whereby patients exhibiting enhanced IL17RLP gene expression willexperience a worse clinical outcome relative to patients expressing thegene at a level nearer the standard level.

[0173] By “assaying the expression level of the gene encoding theIL17RLP protein” is intended qualitatively or quantitatively measuringor estimating the level of the IL17RLP protein or the level of the mRNAencoding the IL17RLP protein in a first biological sample eitherdirectly (e.g., by determining or estimating absolute protein level ormRNA level) or relatively (e.g., by comparing to the IL17RLP proteinlevel or mRNA level in a second biological sample). Preferably, theIL17RLP protein level or mRNA level in the first biological sample ismeasured or estimated and compared to a standard IL17RLP protein levelor mRNA level, the standard being taken from a second biological sampleobtained from an individual not having the disorder or being determinedby averaging levels from a population of individuals not having adisorder of the immune system. As will be appreciated in the art, once astandard IL17RLP protein level or mRNA level is known, it can be usedrepeatedly as a standard for comparison.

[0174] By “biological sample” is intended any biological sample obtainedfrom an individual, body fluid, cell line, tissue culture, or othersource which contains IL17RLP protein or mRNA. As indicated, biologicalsamples include body fluids (such as sera, plasma, urine, synovial fluidand spinal fluid) which contain free extracellular domains of IL17RLPprotein, immune system tissue, and other tissue sources found to expresscomplete, mature or extracellular domain of the IL17RLP. Methods forobtaining tissue biopsies and body fluids from mammals are well known inthe art. Where the biological sample is to include mRNA, a tissue biopsyis the preferred source.

[0175] The present invention is useful for diagnosis or treatment ofvarious immune system-related disorders in mammals, preferably humans.Such disorders include tumors, cancers, interstitial lung disease (suchas Langerhans cell granulomatosis), and any disregulation of immune cellfunction including, but not limited to, autoimmunity, arthritis,leukemias, lymphomas, immunosuppression, immunity, humoral immunity,inflammatory bowel disease, myelo suppression, and the like.

[0176] Total cellular RNA can be isolated from a biological sample usingany suitable technique such as the single-stepguanidinium-thiocyanate-phenol-chloroform method described byChomczynski and Sacchi (Anal. Biochem. 162:156-159 (1987)). Levels ofmRNA encoding the IL17RLP protein are then assayed using any appropriatemethod. These include Northern blot analysis, S1 nuclease mapping, thepolymerase chain reaction (PCR), reverse transcription in combinationwith the polymerase chain reaction (RT-PCR), and reverse transcriptionin combination with the ligase chain reaction (RT-LCR).

[0177] Assaying IL17RLP protein levels in a biological sample can occurusing antibody-based techniques. For example, IL17RLP protein expressionin tissues can be studied with classical immunohistological methods(Jalkanen, M., et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M.,et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-basedmethods useful for detecting IL17RLP protein gene expression includeimmunoassays, such as the enzyme linked immunosorbent assay (ILISA) andthe radioimmunoassay (RIA). Suitable antibody assay labels are known inthe art and include enzyme labels, such as, glucose oxidase, andradioisotopes, such as iodine (¹²⁵I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S),tritium (³H), indium (¹¹²In), and technetium (^(99m)Tc), and fluorescentlabels, such as fluorescein and rhodamine, and biotin.

[0178] In addition to assaying IL17RLP protein levels in a biologicalsample obtained from an individual, IL17RLP protein can also be detectedin vivo by imaging. Antibody labels or markers for in vivo imaging ofIL17RLP protein include those detectable by X-radiography, NMR or ESR.For X-radiography, suitable labels include radioisotopes such as bariumor cesium, which emit detectable radiation but are not overtly harmfulto the subject. Suitable markers for NMR and ESR include those with adetectable characteristic spin, such as deuterium, which may beincorporated into the antibody by labeling of nutrients for the relevanthybridoma.

[0179] A IL17RLP protein-specific antibody or antibody fragment whichhas been labeled with an appropriate detectable imaging moiety, such asa radioisotope (for example, ¹³¹I, ¹¹²In, ^(99m)Tc), a radio-opaquesubstance, or a material detectable by nuclear magnetic resonance, isintroduced (for example, parenterally, subcutaneously orintraperitoneally) into the mammal to be examined for immune systemdisorder. It will be understood in the art that the size of the subjectand the imaging system used will determine the quantity of imagingmoiety needed to produce diagnostic images. In the case of aradioisotope moiety, for a human subject, the quantity of radioactivityinjected will normally range from about 5 to 20 millicuries of ^(99m)Tc.The labeled antibody or antibody fragment will then preferentiallyaccumulate at the location of cells which contain IL17RLP protein. Invivo tumor imaging is described by Burchiel and coworkers (Chapter 13 inTumor Imaging: The Radiochemical Detection of Cancer, Burchiel, S. W.and Rhodes, B. A., eds., Masson Publishing Inc. (1982)).

[0180] Treatment

[0181] As noted above, IL17RLP polynucleotides and polypeptides areuseful for diagnosis of conditions involving abnormally high or lowexpression of IL17RLP activities. Given the cells and tissues whereIL17RLP is expressed as well as the activities modulated by IL17RLP, itis readily apparent that a substantially altered (increased ordecreased) level of expression of IL17RLP in an individual compared tothe standard or “normal” level produces pathological conditions relatedto the bodily system(s) in which IL17RLP is expressed and/or is active.

[0182] It will also be appreciated by one of ordinary skill that, sincethe IL17RLP protein of the invention is a member of the interleukin(IL)-17 receptor family, the extracellular domain of the protein may bereleased in soluble form from the cells which express the IL17RLP byproteolytic cleavage. Therefore, when IL17RLP soluble extracellulardomain is added from an exogenous source to cells, tissues or the bodyof an individual, the protein will exert its physiological activities onits target cells of that individual. Also, cells expressing thistransmembrane protein may be added to cells, tissues or the body of anindividual and these added cells will bind to cells expressing IL17RLP,whereby the cells expressing IL17RLP can cause actions (e.g. cellstimulation) on the ligand-bearing target cells.

[0183] Therefore, it will be appreciated that conditions caused by adecrease in the standard or normal level of IL17RLP activity in anindividual, particularly disorders of the immune system, can be treatedby administration of IL17RLP polypeptide (in the form of a solubleextracellular domain or cells expressing the complete protein). Thus,the invention also provides a method of treatment of an individual inneed of an increased level of IL17RLP activity comprising administeringto such an individual a pharmaceutical composition comprising an amountof an isolated IL17RLP polypeptide of the invention, particularly anextracellular domain of the IL17RLP protein of the invention, effectiveto increase the IL17RLP activity level in such an individual.

[0184] Since IL17RLP is a novel homologue of the recently describedIL-17 receptor, it will have a wide range of cytokine receptor-likeactivities. IL17RLP, or agonists of IL17RLP, may be employed to enhancehost defenses against resistant chronic and acute infections, forexample, mycobacterial infections via the attraction and activation ofmicrobicidal leukocytes. IL17RLP may also be employed to increase T-cellproliferation by the stimulation of IL-2 biosynthesis for the treatmentof T-cell mediated auto-immune diseases and lymphocytic leukemias.IL17RLP may also be employed to regulate hematopoiesis, by regulatingthe activation and differentiation of various hematopoietic progenitorcells, for example, to release mature leukocytes from the bone marrowfollowing chemotherapy, i.e., in stem cell mobilization. IL17RLP mayalso be employed to treat sepsis. Soluble IL17RLP extracellular domainsmay be used as antagonists for IL17RLP activity, and, as such, will beuseful therapeutically, as a mechanism to regulate the activity ofendogenous IL17RLP. Also, stimulation of IL17RLP strongly induces IL-6expression. IL-6 is a potent growth factor for myelomas, plasmacytomas,and hybridomas and is involved in the growth of Lennert's LymphomaT-cells. As a result, IL17RLP agonists and soluble IL17RLP extracellulardomains may be used in the treatment of such cancers, analogous diseasestates, and others known to those of skill in the art.

[0185] Formulations

[0186] The IL17RLP polypeptide composition will be formulated and dosedin a fashion consistent with good medical practice, taking into accountthe clinical condition of the individual patient (especially the sideeffects of treatment with IL17RLP polypeptide alone), the site ofdelivery of the IL17RLP polypeptide composition, the method ofadministration, the scheduling of administration, and other factorsknown to practitioners. The “effective amount” of IL17RLP polypeptidefor purposes herein is thus determined by such considerations.

[0187] As a general proposition, the total pharmaceutically effectiveamount of IL17RLP polypeptide administered parenterally per dose will bein the range of about 1 μg/kg/day to 10 mg/kg/day of patient bodyweight, although, as noted above, this will be subject to therapeuticdiscretion. More preferably, this dose is at least 0.01 mg/kg/day, andmost preferably for humans between about 0.01 and 1 mg/kg/day for thehormone. If given continuously, the IL17RLP polypeptide is typicallyadministered at a dose rate of about 1 μg/kg/hour to about 50μg/kg/hour, either by 1-4 injections per day or by continuoussubcutaneous infusions, for example, using a mini-pump. An intravenousbag solution may also be employed. The length of treatment needed toobserve changes and the interval following treatment for responses tooccur appears to vary depending on the desired effect.

[0188] Pharmaceutical compositions containing the IL17RLP of theinvention may be administered orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, drops or transdermal patch), bucally, or as an oralor nasal spray. By “pharmaceutically acceptable carrier” is meant anon-toxic solid, semisolid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliary of any type. The term “parenteral” asused herein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

[0189] The IL17RLP polypeptide is also suitably administered bysustained-release systems. Suitable examples of sustained-releasecompositions include semi-permeable polymer matrices in the form ofshaped articles, e.g., films, or mirocapsules. Sustained-releasematrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481),copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U.,et al., Biopolymers 22:547-556 (1983)), poly (2-hydroxyethylmethacrylate; Langer, R., et al., J. Biomed. Mater. Res. 15:167-277(1981), and Langer, R., Chem. Tech. 12:98-105 (1982)), ethylene vinylacetate (Langer, R., et al., Id.) or poly-D-(−)-3-hydroxybutyric acid(EP 133,988). Sustained-release IL17RLP polypeptide compositions alsoinclude liposomally entrapped IL17RLP polypeptide. Liposomes containingIL17RLP polypeptide are prepared by methods known in the art (DE3,218,121; Epstein, et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692(1985); Hwang, et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980);EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat.Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP102,324). Ordinarily, the liposomes are of the small (about 200-800Angstroms) unilamellar type in which the lipid content is greater thanabout 30 mol. percent cholesterol, the selected proportion beingadjusted for the optimal IL17RLP polypeptide therapy.

[0190] For parenteral administration, in one embodiment, the IL17RLPpolypeptide is formulated generally by mixing it at the desired degreeof purity, in a unit dosage injectable form (solution, suspension, oremulsion), with a pharmaceutically acceptable carrier, i.e., one that isnon-toxic to recipients at the dosages and concentrations employed andis compatible with other ingredients of the formulation. For example,the formulation preferably does not include oxidizing agents and othercompounds that are known to be deleterious to polypeptides.

[0191] Generally, the formulations are prepared by contacting theIL17RLP polypeptide uniformly and intimately with liquid carriers orfinely divided solid carriers or both. Then, if necessary, the productis shaped into the desired formulation. Preferably the carrier is aparenteral carrier, more preferably a solution that is isotonic with theblood of the recipient. Examples of such carrier vehicles include water,saline, Ringer's solution, and dextrose solution. Non-aqueous vehiclessuch as fixed oils and ethyl oleate are also useful herein, as well asliposomes.

[0192] The carrier suitably contains minor amounts of additives such assubstances that enhance isotonicity and chemical stability. Suchmaterials are non-toxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate, succinate,acetic acid, and other organic acids or their salts; antioxidants suchas ascorbic acid; low molecular weight (less than about ten residues)polypeptides, e.g., polyarginine or tripeptides; proteins, such as serumalbumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids, such as glycine, glutamic acid,aspartic acid, or arginine; monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, manose,or dextrins; chelating agents such as EDTA; sugar alcohols such asmannitol or sorbitol; counterions such as sodium; and/or nonionicsurfactants such as polysorbates, poloxamers, or PEG.

[0193] The IL17RLP polypeptide is typically formulated in such vehiclesat a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10mg/ml, at a pH of about 3 to 8. It will be understood that the use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of IL17RLP polypeptide salts.

[0194] IL17RLP polypeptide to be used for therapeutic administrationmust be sterile. Sterility is readily accomplished by filtration throughsterile filtration membranes (e.g., 0.2 micron membranes). TherapeuticIL17RLP polypeptide compositions generally are placed into a containerhaving a sterile access port, for example, an intravenous solution bagor vial having a stopper pierceable by a hypodermic injection needle.

[0195] IL17RLP polypeptide ordinarily will be stored in unit ormulti-dose containers, for example, sealed ampoules or vials, as anaqueous solution or as a lyophilized formulation for reconstitution. Asan example of a lyophilized formulation, 10-ml vials are filled with 5ml of sterile-filtered 1% (w/v) aqueous IL17RLP polypeptide solution,and the resulting mixture is lyophilized. The infusion solution isprepared by reconstituting the lyophilized IL17RLP polypeptide usingbacteriostatic water-for-injection (WFI).

[0196] The invention also provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention.Associated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration. Inaddition, the polypeptides of the present invention may be employed inconjunction with other therapeutic compounds.

[0197] Agonists and Antagonists—Assays and Molecules

[0198] The invention also provides a method of screening compounds toidentify those which enhance or block the action of IL17RLP on cells,such as its interaction with IL17RLP-binding molecules such as ligandmolecules. An agonist is a compound which increases the naturalbiological functions of IL17RLP or which functions in a manner similarto IL17RLP, while antagonists decrease or eliminate such functions.

[0199] In another aspect of this embodiment the invention provides amethod for identifying a ligand protein which binds specifically to aIL17RLP polypeptide. For example, a cellular compartment, such as amembrane or a preparation thereof, may be prepared from a cell thatexpresses a molecule that binds IL17RLP. The preparation is incubatedwith labeled IL17RLP and complexes of IL17RLP bound to the ligand orother binding protein are isolated and characterized according toroutine methods known in the art. Alternatively, the IL17RLP polypeptidemay be bound to a solid support so that binding molecules solubilizedfrom cells are bound to the column and then eluted and characterizedaccording to routine methods.

[0200] In the assay of the invention for agonists or antagonists, acellular compartment, such as a membrane or a preparation thereof, maybe prepared from a cell that expresses a molecule that binds IL17RLP,such as a molecule of a signaling or regulatory pathway modulated byIL17RLP. The preparation is incubated with labeled IL17RLP in theabsence or the presence of a candidate molecule which may be a IL17RLPagonist or antagonist. The ability of the candidate molecule to bind thebinding molecule is reflected in decreased binding of the labeledligand. Molecules which bind gratuitously, i.e., without inducing theeffects of IL17RLP on binding the IL17RLP binding molecule, are mostlikely to be good antagonists. Molecules that bind well and eliciteffects that are the same as or closely related to IL17RLP are agonists.

[0201] IL17RLP-like effects of potential agonists and antagonists may bymeasured, for instance, by determining activity of a second messengersystem following interaction of the candidate molecule with a cell orappropriate cell preparation, and comparing the effect with that ofIL17RLP or molecules that elicit the same effects as IL17RLP. Secondmessenger systems that may be useful in this regard include but are notlimited to AMP guanylate cyclase, ion channel or phosphoinositidehydrolysis second messenger systems.

[0202] Another example of an assay for IL17RLP antagonists is acompetitive assay that combines an IL17RLP ligand and a potentialantagonist with membrane-bound IL17RLP receptor molecules or recombinantIL17RLP receptor molecules under appropriate conditions for acompetitive inhibition assay. The IL17RLP ligand can be labeled, such asby radioactivity, such that the number of IL17RLP ligand molecules boundto a receptor molecule can be determined accurately to assess theeffectiveness of the potential antagonist.

[0203] Potential antagonists include small organic molecules, peptides,polypeptides and antibodies that bind to a polypeptide of the inventionand thereby inhibit or extinguish its activity. Potential antagonistsalso may be small organic molecules, a peptide, a polypeptide such as aclosely related protein or antibody that binds the same sites on abinding molecule, without inducing IL17RLP-induced activities, therebypreventing the action of IL17RLP by excluding the IL17RLP ligand frombinding.

[0204] Other potential antagonists include antisense molecules.Antisense technology can be used to control gene expression throughantisense DNA or RNA or through triple-helix formation. Antisensetechniques are discussed in a number of studies (for example, Okano, J.Neurochem. 56:560 (1991); “Oligodeoxynucleotides as Antisense Inhibitorsof Gene Expression.” CRC Press, Boca Raton, Fla. (1988)). Triple helixformation is discussed in a number of studies, as well (for instance,Lee, et al., Nucleic Acids Research 6:3073 (1979); Cooney, et al.,Science 241:456 (1988); Dervan, et al., Science 251:1360 (1991)). Themethods are based on binding of a polynucleotide to a complementary DNAor RNA. For example, the 5′ coding portion of a polynucleotide thatencodes the mature polypeptide of the present invention may be used todesign an antisense RNA oligonucleotide of from about 10 to 40 basepairs in length. A DNA oligonucleotide is designed to be complementaryto a region of the gene involved in transcription thereby preventingtranscription and the production of IL17RLP. The antisense RNAoligonucleotide hybridizes to the mRNA in vivo and blocks translation ofthe mRNA molecule into IL17RLP polypeptide. The oligonucleotidesdescribed above can also be delivered to cells such that the antisenseRNA or DNA may be expressed in vivo to inhibit production of IL17RLPprotein.

[0205] The agonists and antagonists may be employed in a compositionwith a pharmaceutically acceptable carrier, e.g., as described above.

[0206] The antagonists may be employed for instance to inhibit theactivation of macrophages and their precursors, and of neutrophils,basophils, B lymphocytes and some T-cell subsets, e.g., activated andCD8 cytotoxic T cells and natural killer cells, in certain auto-immuneand chronic inflammatory and infective diseases. Examples of auto-immunediseases include multiple sclerosis, and insulin-dependent diabetes. Theantagonists may also be employed to treat infectious diseases includingsilicosis, sarcoidosis, idiopathic pulmonary fibrosis by preventing theactivation of mononuclear phagocytes. They may also be employed to treatidiopathic hyper-eosinophilic syndrome by preventing eosinophilproduction. Antagonists may also be employed to treat rheumatoidarthritis by preventing the activation of monocytes in the synovialfluid in the joints of patients. Monocyte activation plays a significantrole in the pathogenesis of both degenerative and inflammatoryarthropathies. The antagonists may be employed to interfere with thedeleterious cascades attributed primarily to IL-1 and TNF, whichprevents the biosynthesis of other inflammatory cytokines. In this way,the antagonists may be employed to prevent inflammation. Antibodiesagainst IL17RLP may be employed to bind to and inhibit IL17RLP activityto treat such conditions described above. Any of the above antagonistsmay be employed in a composition with a pharmaceutically acceptablecarrier, e.g., as hereinafter described.

[0207] Gene Mapping

[0208] The nucleic acid molecules of the present invention are alsovaluable for chromosome identification. The sequence is specificallytargeted to and can hybridize with a particular location on anindividual human chromosome. Moreover, there is a current need foridentifying particular sites on the chromosome. Few chromosome markingreagents based on actual sequence data (repeat polymorphisms) arepresently available for marking chromosomal location. The mapping ofDNAs to chromosomes according to the present invention is an importantfirst step in correlating those sequences with genes associated withdisease.

[0209] In certain preferred embodiments in this regard, the cDNA hereindisclosed is used to clone genomic DNA of a IL17RLP protein gene. Thiscan be accomplished using a variety of well known techniques andlibraries, which generally are available commercially. The genomic DNAthen is used for in situ chromosome mapping using well known techniquesfor this purpose.

[0210] In addition, in some cases, sequences can be mapped tochromosomes by preparing PCR primers (preferably 15-25 bp) from thecDNA. Computer analysis of the 3′ untranslated region of the gene isused to rapidly select primers that do not span more than one exon inthe genomic DNA, thus complicating the amplification process. Theseprimers are then used for PCR screening of somatic cell hybridscontaining individual human chromosomes. Fluorescence in situhybridization (“FISH”) of a cDNA clone to a metaphase chromosomal spreadcan be used to provide a precise chromosomal location in one step. Thistechnique can be used with probes from the cDNA as short as 50 or 60 bp(for a review of this technique, see Verma, et al., Human Chromosomes: AManual Of Basic Techniques, Pergamon Press, New York (1988)).

[0211] Once a sequence has been mapped to a precise chromosomallocation, the physical position of the sequence on the chromosome can becorrelated with genetic map data. Such data are found, for example, onthe World Wide Web (McKusick, V. Mendelian Inheritance In Man, availableon-line through Johns Hopkins University, Welch Medical Library). Therelationship between genes and diseases that have been mapped to thesame chromosomal region are then identified through linkage analysis(coinheritance of physically adjacent genes).

[0212] Next, it is necessary to determine the differences in the cDNA orgenomic sequence between affected and unaffected individuals. If amutation is observed in some or all of the affected individuals but notin any normal individuals, then the mutation is likely to be thecausative agent of the disease.

[0213] Having generally described the invention, the same will be morereadily understood by reference to the following examples, which areprovided by way of illustration and are not intended as limiting.

EXAMPLES Example 1(a) Expression and Purification of “His-Tagged”IL17RLP in E. coli

[0214] The bacterial expression vector pQE9 (pD10) is used for bacterialexpression in this example. (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth,Calif., 91311). pQE9 encodes ampicillin antibiotic resistance (“Ampr”)and contains a bacterial origin of replication (“ori”), an IPTGinducible promoter, a ribosome binding site (“RBS”), six codons encodinghistidine residues that allow affinity purification usingnickel-nitrilo-tri-acetic acid (“Ni—NTA”) affinity resin sold by QIAGEN,Inc., supra, and suitable single restriction enzyme cleavage sites.These elements are arranged such that an inserted DNA fragment encodinga polypeptide expresses that polypeptide with the six His residues(i.e., a “6×His tag”) covalently linked to the amino terminus of thatpolypeptide.

[0215] The DNA sequence encoding the desired portion of the IL17RLPprotein comprising the extracellular domain of the IL17RLP amino acidsequence is amplified from the deposited cDNA clone using PCRoligonucleotide primers which anneal to the amino terminal sequences ofthe desired portion of the IL17RLP protein and to sequences in thedeposited construct 3′ to the cDNA coding sequence. Additionalnucleotides containing restriction sites to facilitate cloning in thepQE9 vector are added to the 5′ and 3′ primer sequences, respectively.

[0216] For cloning the extracellular domain of the IL17RLP protein, the5′ primer has the sequence 5′ CGC CCA TGG CCG ACC GTT CAA TGT GGC TCTGAA AC 3′ (SEQ ID NO:6) containing the underlined Nco I restriction sitefollowed by 26 nucleotides of the amino terminal coding sequence of themature IL17RLP sequence in SEQ ID NO:2. One of ordinary skill in the artwould appreciate, of course, that the point in the protein codingsequence where the 5′ primer begins may be varied to amplify a DNAsegment encoding any desired portion of the complete IL17RLP proteinshorter or longer than the extracellular domain of the protein. The 3′primer has the sequence 5′ CGC AAG CTT CCA GCC TCC CGG CTT GC 3′ (SEQ IDNO:7) containing the underlined Hind III restriction site followed by 17nucleotides complementary to the 3′ end of the coding sequence of theIL17RLP DNA sequence in FIGS. 1A, 1B, and 1C.

[0217] The amplified IL17RLP DNA fragment and the vector pQE9 aredigested with Nco I and Hind III and the digested DNAs are then ligatedtogether. Insertion of the IL17RLP DNA into the restricted pQE9 vectorplaces the IL17RLP protein coding region downstream from theIPTG-inducible promoter and in-frame with an initiating AUG and the sixhistidine codons.

[0218] The ligation mixture is transformed into competent E. coli cellsusing standard procedures such as those described by Sambrook andcolleagues (Molecular Cloning: a Laboratory Manual, 2nd Ed.; Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)). E. colistrain M15/rep4, containing multiple copies of the plasmid pREP4, whichexpresses the lac repressor and confers kanamycin resistance (“Kanr”),is used in carrying out the illustrative example described herein. Thisstrain, which is only one of many that are suitable for expressingIL17RLP protein, is available commercially (QIAGEN, Inc., supra).Transformants are identified by their ability to grow on LB plates inthe presence of ampicillin and kanamycin. Plasmid DNA is isolated fromresistant colonies and the identity of the cloned DNA confirmed byrestriction analysis, PCR and DNA sequencing.

[0219] Clones containing the desired constructs are grown overnight(“O/N”) in liquid culture in LB media supplemented with both ampicillin(100 μg/ml) and kanamycin (25 μg/ml). The O/N culture is used toinoculate a large culture, at a dilution of approximately 1:25 to 1:250.The cells are grown to an optical density at 600 nm (“OD600”) of between0.4 and 0.6. Isopropyl-β-D-thiogalactopyranoside (“IPTG”) is then addedto a final concentration of 1 mM to induce transcription from the lacrepressor sensitive promoter, by inactivating the lacI repressor. Cellssubsequently are incubated further for 3 to 4 hours. Cells then areharvested by centrifugation.

[0220] The cells are then stirred for 3-4 hours at 4° C. in 6Mguanidine-HCl, pH 8. The cell debris is removed by centrifugation, andthe supernatant containing the IL17RLP is loaded onto anickel-nitrilo-tri-acetic acid (“Ni—NTA”) affinity resin column (QIAGEN,Inc., supra). Proteins with a 6×His tag bind to the Ni-NTA resin withhigh affinity and can be purified in a simple one-step procedure (fordetails see: The QIAexpressionist, 1995, QIAGEN, Inc., supra). Brieflythe supernatant is loaded onto the column in 6 M guanidine-HCl, pH 8,the column is first washed with 10 volumes of 6 M guanidine-HCl, pH 8,then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finally theIL17RLP is eluted with 6 M guanidine-HCl, pH 5.

[0221] The purified protein is then renatured by dialyzing it againstphosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus200 mM NaCl. Alternatively, the protein can be successfully refoldedwhile immobilized on the Ni—NTA column. The recommended conditions areas follows: renature using a linear 6M-1M urea gradient in 500 mM NaCl,20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors. Therenaturation should be performed over a period of 1.5 hours or more.After renaturation the proteins can be eluted by the addition of 250 mMimmidazole. Immidazole is removed by a final dialyzing step against PBSor 50 mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purifiedprotein is stored at 4° C. or frozen at −80° C.

[0222] The following alternative method may be used to purify IL17RLPexpressed in E. coli when it is present in the form of inclusion bodies.Unless otherwise specified, all of the following steps are conducted at4-10° C.

[0223] Upon completion of the production phase of the E. colifermentation, the cell culture is cooled to 4-10° C. and the cells areharvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech).On the basis of the expected yield of protein per unit weight of cellpaste and the amount of purified protein required, an appropriate amountof cell paste, by weight, is suspended in a buffer solution containing100 mM Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to ahomogeneous suspension using a high shear mixer.

[0224] The cells ware then lysed by passing the solution through amicrofluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at4000-6000 psi. The homogenate is then mixed with NaCl solution to afinal concentration of 0.5 M NaCl, followed by centrifugation at 7000×gfor 15 min. The resultant pellet is washed again using 0.5M NaCl, 100 mMTris, 50 mM EDTA, pH 7.4.

[0225] The resulting washed inclusion bodies are solubilized with 1.5 Mguanidine hydrochloride (GuHCl) for 2-4 hours. After 7000×gcentrifugation for 15 min., the pellet is discarded and the IL17RLPpolypeptide-containing supernatant is incubated at 4° C. overnight toallow further GuHCl extraction.

[0226] Following high speed centrifugation (30,000×g) to removeinsoluble particles, the GuHCl solubilized protein is refolded byquickly mixing the GuHCl extract with 20 volumes of buffer containing 50mM sodium, pH 4.5, 150 mM NaCl, 2 mM EDTA by vigorous stirring. Therefolded diluted protein solution is kept at 4° C. without mixing for 12hours prior to further purification steps.

[0227] To clarify the refolded IL17RLP polypeptide solution, apreviously prepared tangential filtration unit equipped with 0.16 μmmembrane filter with appropriate surface area (e.g., Filtron),equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The filteredsample is loaded onto a cation exchange resin (e.g., Poros HS-50,Perseptive Biosystems). The column is washed with 40 mM sodium acetate,pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCl in thesame buffer, in a stepwise manner. The absorbance at 280 mm of theeffluent is continuously monitored. Fractions are collected and furtheranalyzed by SDS-PAGE.

[0228] Fractions containing the IL17RLP polypeptide are then pooled andmixed with 4 volumes of water. The diluted sample is then loaded onto apreviously prepared set of tandem columns of strong anion (Poros HQ-50,Perseptive Biosystems) and weak anion (Poros CM-20, PerseptiveBiosystems) exchange resins. The columns are equilibrated with 40 mMsodium acetate, pH 6.0. Both columns are washed with 40 mM sodiumacetate, pH 6.0, 200 mM NaCl. The CM-20 column is then eluted using a 10column volume linear gradient ranging from 0.2 M NaCl, 50 mM sodiumacetate, pH 6.0 to 1.0 M NaCl, 50 mM sodium acetate, pH 6.5. Fractionsare collected under constant A₂₈₀ monitoring of the effluent. Fractionscontaining the IL17RLP polypeptide (determined, for instance, by 16%SDS-PAGE) are then pooled.

[0229] The resultant IL17RLP polypeptide exhibits greater than 95%purity after the above refolding and purification steps. No majorcontaminant bands are observed from Commassie blue stained 16% SDS-PAGEgel when 5 μg of purified protein is loaded. The purified protein isalso tested for endotoxin/LPS contamination, and typically the LPScontent is less than 0.1 ng/ml according to LAL assays.

Example 2 Cloning and Expression of IL17RLP Protein in a BaculovirusExpression System

[0230] In this illustrative example, the plasmid shuttle vector pA2 isused to insert the cloned DNA encoding complete protein, including itsnaturally associated secretory signal (leader) sequence, into abaculovirus to express the mature IL17RLP protein, using standardmethods as described by Summers and colleagues (A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures, TexasAgricultural Experimental Station Bulletin No. 1555 (1987)). Thisexpression vector contains the strong polyhedrin promoter of theAutographa californica nuclear polyhedrosis virus (AcMNPV) followed byconvenient restriction sites such as Bam HI, Xba I and Asp 718. Thepolyadenylation site of the simian virus 40 (“SV40”) is used forefficient polyadenylation. For easy selection of recombinant virus, theplasmid contains the beta-galactosidase gene from E. coli under controlof a weak Drosophila promoter in the same orientation, followed by thepolyadenylation signal of the polyhedrin gene. The inserted genes areflanked on both sides by viral sequences for cell-mediated homologousrecombination with wild-type viral DNA to generate a viable virus thatexpress the cloned polynucleotide.

[0231] Many other baculovirus vectors could be used in place of thevector above, such as pAc373, pVL941 and pAcIM1, as one skilled in theart would readily appreciate, as long as the construct providesappropriately located signals for transcription, translation, secretionand the like, including a signal peptide and an in-frame AUG asrequired. Such vectors are described, for instance, by Luckow andcoworkers (Virology 170:31-39 (1989)).

[0232] The cDNA sequence encoding the extracellular domain of theIL17RLP protein in the deposited clone, including the AUG initiationcodon and the naturally associated leader sequence shown in SEQ ID NO:2,is amplified using PCR oligonucleotide primers corresponding to the 5′and 3′ sequences of the gene. The 5′ primer has the sequence 5′ CGC GGATCC ATG TCG CTC GTG CTG CTA AGC CTG G 3′ (SEQ ID NO:8) containing theunderlined Bam HI restriction enzyme site, an efficient signal forinitiation of translation in eukaryotic cells (Kozak, M., J. Mol. Biol.196:947-950 (1987)), followed by 25 of nucleotides of the sequence ofthe complete IL17RLP protein shown in FIGS. 1A, 1B, and 1C, beginningwith the AUG initiation codon. The 3′ primer has the sequence 5′ CGC GGTACC CCA GCC TCC CGG CTT GC 3′ (SEQ ID NO:9) containing the underlinedAsp 718 restriction site followed by 17 nucleotides complementary to the3′ noncoding sequence in FIGS. 1A, 1B, and 1C.

[0233] The amplified fragment is isolated from a 1% agarose gel using acommercially available kit (“Geneclean,” BIO 101 Inc., La Jolla,Calif.). The fragment then is digested with Bam HI and Asp 718 and againis purified on a 1% agarose gel. This fragment is designated herein F1.

[0234] The plasmid is digested with the restriction enzymes Bam HI andAsp 718 and optionally, can be dephosphorylated using calf intestinalphosphatase, using routine procedures known in the art. The DNA is thenisolated from a 1% agarose gel using a commercially available kit(“Geneclean” BIO 101 Inc., La Jolla, Calif.). This vector DNA isdesignated herein “V1”.

[0235] Fragment F1 and the dephosphorylated plasmid V1 are ligatedtogether with T4 DNA ligase. E. coli HB101 or other suitable E. colihosts such as XL-1 Blue (Statagene Cloning Systems, La Jolla, Calif.)cells are transformed with the ligation mixture and spread on cultureplates. Bacteria are identified that contain the plasmid with the humanIL17RLP gene by digesting DNA from individual colonies using Bam HI andAsp 718 and then analyzing the digestion product by gel electrophoresis.The sequence of the cloned fragment is confirmed by DNA sequencing. Thisplasmid is designated herein pA2IL17RLP.

[0236] Five μg of the plasmid pA2IL17RLP is co-transfected with 1.0 μgof a commercially available linearized baculovirus DNA (“BaculoGold™baculovirus DNA”, Pharmingen, San Diego, Calif.), using the lipofectionmethod described by Felgner and colleaguew (Proc. Natl. Acad. Sci. USA84:7413-7417 (1987)). One μg of BaculoGold™ virus DNA and 5 μg of theplasmid pA2IL17RLP are mixed in a sterile well of a microtiter platecontaining 50 μl of serum-free Grace's medium (Life Technologies Inc.,Gaithersburg, Md.). Afterwards, 10 μl Lipofectin plus 90 μl Grace'smedium are added, mixed and incubated for 15 minutes at roomtemperature. Then the transfection mixture is added drop-wise to Sf9insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with1 ml Grace's medium without serum. The plate is then incubated for 5hours at 27° C. The transfection solution is then removed from the plateand 1 ml of Grace's insect medium supplemented with 10% fetal calf serumis added. Cultivation is then continued at 27° C. for four days.

[0237] After four days the supernatant is collected and a plaque assayis performed, as described by Summers and Smith (supra). An agarose gelwith “Blue Gal” (Life Technologies Inc., Gaithersburg) is used to alloweasy identification and isolation of gal-expressing clones, whichproduce blue-stained plaques. (A detailed description of a “plaqueassay” of this type can also be found in the user's guide for insectcell culture and baculovirology distributed by Life Technologies Inc.,Gaithersburg, page 9-10). After appropriate incubation, blue stainedplaques are picked with the tip of a micropipettor (e.g., Eppendorf).The agar containing the recombinant viruses is then resuspended in amicrocentrifuge tube containing 200 μl of Grace's medium and thesuspension containing the recombinant baculovirus is used to infect Sf9cells seeded in 35 mm dishes. Four days later the supernatants of theseculture dishes are harvested and then they are stored at 4° C. Therecombinant virus is called V-IL17RLP.

[0238] To verify the expression of the IL17RLP gene Sf9 cells are grownin Grace's medium supplemented with 10% heat-inactivated FBS. The cellsare infected with the recombinant baculovirus V-IL17RLP at amultiplicity of infection (“MOI”) of about 2. If radiolabeled proteinsare desired, 6 hours later the medium is removed and is replaced withSF900 II medium minus methionine and cysteine (available from LifeTechnologies Inc., Rockville, Md.). After 42 hours, 5 μCi of³⁵S-methionine and 5 μCi ³⁵S-cysteine (available from Amersham) areadded. The cells are further incubated for 16 hours and then areharvested by centrifugation. The proteins in the supernatant as well asthe intracellular proteins are analyzed by SDS-PAGE followed byautoradiography (if radiolabeled).

[0239] Microsequencing of the amino acid sequence of the amino terminusof purified protein may be used to determine the amino terminal sequenceof the extracellular domain of the IL17RLP protein, and thus thecleavage point and length of the naturally associated secretory signalpeptide.

Example 3 Cloning and Expression of IL17RLP in Mammalian Cells

[0240] A typical mammalian expression vector contains the promoterelement, which mediates the initiation of transcription of mRNA, theprotein coding sequence, and signals required for the termination oftranscription and polyadenylation of the transcript. Additional elementsinclude enhancers, Kozak sequences and intervening sequences flanked bydonor and acceptor sites for RNA splicing. Highly efficienttranscription can be achieved with the early and late promoters fromSV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV,HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV).However, cellular elements can also be used (e.g., the human actinpromoter). Suitable expression vectors for use in practicing the presentinvention include, for example, vectors such as pSVL and pMSG(Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC37146) and pBC12MI (ATCC 67109). Mammalian host cells that could be usedinclude, human Hela, 293, H9 and Jurkat cells, mouse NIH3T3 and C127cells, Cos 1, Cos 7 and CV1, quail QC1-3 cells, mouse L cells andChinese hamster ovary (CHO) cells.

[0241] Alternatively, the gene can be expressed in stable cell linesthat contain the gene integrated into a chromosome. The co-transfectionwith a selectable marker such as dhfr, gpt, neomycin, hygromycin allowsthe identification and isolation of the transfected cells.

[0242] The transfected gene can also be amplified to express largeamounts of the encoded protein. The DHFR (dihydrofolate reductase)marker is useful to develop cell lines that carry several hundred oreven several thousand copies of the gene of interest. Another usefulselection marker is the enzyme glutamine synthase (GS; Murphy, et al.,Biochem J. 227:277-279 (1991); Bebbington, et al., Bio/Technology10:169-175 (1992)). Using these markers, the mammalian cells are grownin selective medium and the cells with the highest resistance areselected. These cell lines contain the amplified gene(s) integrated intoa chromosome. Chinese hamster ovary (CHO) and NSO cells are often usedfor the production of proteins.

[0243] The expression vectors pC1 and pC4 contain the strong promoter(LTR) of the Rous Sarcoma Virus (Cullen, et al., Mol. Cel. Biol.5:438-447 (1985)) plus a fragment of the CMV-enhancer (Boshart, et al.,Cell 41:521-530 (1985)). Multiple cloning sites, e.g., with therestriction enzyme cleavage sites Bam HI, Xba I and Asp 718, facilitatethe cloning of the gene of interest. The vectors contain in addition the3′ intron, the polyadenylation and termination signal of the ratpreproinsulin gene.

Example 3(a) Cloning and Expression in COS Cells

[0244] The expression plasmid, pIL17RLPHA, is made by cloning a portionof the cDNA encoding the extracelluar domain of the IL17RLP protein intothe expression vector pcDNAI/Amp or pcDNAIII (which can be obtained fromInvitrogen, Inc.).

[0245] The expression vector pcDNAI/amp contains: (1) an E. coli originof replication effective for propagation in E. coli and otherprokaryotic cells; (2) an ampicillin resistance gene for selection ofplasmid-containing prokaryotic cells; (3) an SV40 origin of replicationfor propagation in eukaryotic cells; (4) a CMV promoter, a polylinker,an SV40 intron; (5) several codons encoding a hemagglutinin fragment(i.e., an “HA” tag to facilitate purification) followed by a terminationcodon and polyadenylation signal arranged so that a cDNA can beconveniently placed under expression control of the CMV promoter andoperably linked to the SV40 intron and the polyadenylation signal bymeans of restriction sites in the polylinker. The HA tag corresponds toan epitope derived from the influenza hemagglutinin protein described byWilson and colleagues (Cell 37:767 (1984)). The fusion of the HA tag tothe target protein allows easy detection and recovery of the recombinantprotein with an antibody that recognizes the HA epitope. pcDNAIIIcontains, in addition, the selectable neomycin marker.

[0246] A DNA fragment encoding the extracellular domain of the IL17RLPpolypeptide is cloned into the polylinker region of the vector so thatrecombinant protein expression is directed by the CMV promoter. Theplasmid construction strategy is as follows. The IL17RLP cDNA of thedeposited clone is amplified using primers that contain convenientrestriction sites, much as described above for construction of vectorsfor expression of IL17RLP in E. coli. Suitable primers include thefollowing, which are used in this example. The 5′ primer, containing theunderlined Bam HI site, a Kozak sequence, an AUG start codon, and 25nucleotides of the 5′ coding region of the extracellular domain of theIL17RLP polypeptide, has the following sequence: 5′ GCC GGA TCC GCC ACCATG AAC TCC TTC TCC ACA AGC GCC TTC GGT CCA GTT GCC TTC TCC CTG GGG CTGCTC CTG GTG TTG CCT GCT GCC TTC CCT GCC CCA GTA TGT CGC TCG TGC TGC TAAGCC TGG 3′ (SEQ ID NO: 10). The 3′ primer, containing the underlined Asp718 and 17 of nucleotides complementary to the 3′ coding sequenceimmediately before the stop codon, has the following sequence: 5′ GGCCGG GTA CCC CAG CCT CCC GGC TTG C 3′ (SEQ ID NO:11).

[0247] The PCR amplified DNA fragment and the vector, pcDNAI/Amp, aredigested with Bam HI and Asp 718 and then ligated. The ligation mixtureis transformed into E. coli strain SURE (Stratagene Cloning Systems, LaJolla, Calif. 92037), and the transformed culture is plated onampicillin media plates which then are incubated to allow growth ofampicillin resistant colonies. Plasmid DNA is isolated from resistantcolonies and examined by restriction analysis or other means for thepresence of the fragment encoding the extracellular domain of theIL17RLP polypeptide

[0248] For expression of recombinant IL17RLP, COS cells are transfectedwith an expression vector, as described above, using DEAE-dextran, asdescribed, for instance, by Sambrook and coworkers (Molecular Cloning: aLaboratory Manual, Cold Spring Laboratory Press, Cold Spring Harbor,N.Y. (1989)). Cells are incubated under conditions for expression ofIL17RLP by the vector.

[0249] Expression of the IL17RLP-HA fusion protein is detected byradiolabeling and immunoprecipitation, using methods described in, forexample Harlow and colleagues (Antibodies: A Laboratory Manual, 2nd Ed.;Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988)).To this end, two days after transfection, the cells are labeled byincubation in media containing ³⁵S-cysteine for 8 hours. The cells andthe media are collected, and the cells are washed and the lysed withdetergent-containing RIPA buffer: 150 mM NaCl, 1% NP-40, 0.1% SDS, 1%NP-40, 0.5% DOC, 50 mM TRIS, pH 7.5, as described by Wilson andcolleagues (supra). Proteins are precipitated from the cell lysate andfrom the culture media using an HA-specific monoclonal antibody. Theprecipitated proteins then are analyzed by SDS-PAGE and autoradiography.An expression product of the expected size is seen in the cell lysate,which is not seen in negative controls.

Example 3(b) Cloning and Expression in CHO Cells

[0250] The vector pC4 is used for the expression of IL17RLP polypeptide.Plasmid pC4 is a derivative of the plasmid pSV2-dhfr (ATCC Accession No.37146). The plasmid contains the mouse DHFR gene under control of theSV40 early promoter. Chinese hamster ovary- or other cells lackingdihydrofolate activity that are transfected with these plasmids can beselected by growing the cells in a selective medium (alpha minus MEM,Life Technologies) supplemented with the chemotherapeutic agentmethotrexate. The amplification of the DHFR genes in cells resistant tomethotrexate (MTX) has been well documented (see, e.g., Alt, F. W., etal., J. Biol. Chem. 253:1357-1370 (1978); Hamlin, J. L. and Ma, C.Biochem. et Biophys. Acta, 1097:107-143 (1990); Page, M. J. andSydenham, M. A. Biotechnology 9:64-68 (1991)). Cells grown in increasingconcentrations of MTX develop resistance to the drug by overproducingthe target enzyme, DHFR, as a result of amplification of the DHFR gene.If a second gene is linked to the DHFR gene, it is usually co-amplifiedand over-expressed. It is known in the art that this approach may beused to develop cell lines carrying more than 1,000 copies of theamplified gene(s). Subsequently, when the methotrexate is withdrawn,cell lines are obtained which contain the amplified gene integrated intoone or more chromosome(s) of the host cell.

[0251] Plasmid pC4 contains for expressing the gene of interest thestrong promoter of the long terminal repeat (LTR) of the Rouse SarcomaVirus (Cullen, et al., Mol. Cell. Biol. 5:438-447 (1985)) plus afragment isolated from the enhancer of the immediate early gene of humancytomegalovirus (CMV; Boshart, et al., Cell 41:521-530 (1985)).Downstream of the promoter are the following single restriction enzymecleavage sites that allow the integration of the genes: Bam HI, Xba I,and Asp 718. Behind these cloning sites the plasmid contains the 3′intron and polyadenylation site of the rat preproinsulin gene. Otherhigh efficiency promoters can also be used for the expression, e.g., thehuman β-actin promoter, the SV40 early or late promoters or the longterminal repeats from other retroviruses, e.g., HIV and HTLVI.Clontech's Tet-Off and Tet-On gene expression systems and similarsystems can be used to express the IL17RLP polypeptide in a regulatedway in mammalian cells (Gossen, M., and Bujard, H. Proc. Natl. Acad.Sci. USA 89:5547-5551 (1992)). For the polyadenylation of the mRNA othersignals, e.g., from the human growth hormone or globin genes can be usedas well. Stable cell lines carrying a gene of interest integrated intothe chromosomes can also be selected upon co-transfection with aselectable marker such as gpt, G418 or hygromycin. It is advantageous touse more than one selectable marker in the beginning, e.g., G418 plusmethotrexate.

[0252] The plasmid pC4 is digested with the restriction enzymes Bam HIand Asp 718 and then dephosphorylated using calf intestinal phosphatesby procedures known in the art. The vector is then isolated from a 1%agarose gel.

[0253] The DNA sequence encoding the extracellular domain of the IL17RLPpolypeptide is amplified using PCR oligonucleotide primers correspondingto the 5′ and 3′ sequences of the desired portion of the gene. The 5′primer containing the underlined Bam HI site, a Kozak sequence, an AUGstart codon, and 25 nucleotides of the 5′ coding region of theextracellular domain of the IL17RLP polypeptide, has the followingsequence: 5′ CTA GCC GGA TCC GCC ACC ATG TCG CTC GTG CTG CTA AGC CTG G3′ (SEQ ID NO: 12). The 3′ primer, containing the underlined Asp 718 and17 of nucleotides complementary to the 3′ coding sequence immediatelybefore the stop codon as shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1),has the following sequence: 5′ GGC CGG GTA CCC CAG CCT CCC GGC TTG C 3′(SEQ ID NO:13).

[0254] The amplified fragment is digested with the endonucleases Bam HIand Asp 718 and then purified again on a 1% agarose gel. The isolatedfragment and the dephosphorylated vector are then ligated with T4 DNAligase. E. coli HB101 or XL-1 Blue cells are then transformed andbacteria are identified that contain the fragment inserted into plasmidpC4 using, for instance, restriction enzyme analysis.

[0255] Chinese hamster ovary cells lacking an active DHFR gene are usedfor transfection. Five μg of the expression plasmid pC4 is cotransfectedwith 0.5 μg of the plasmid pSVneo using lipofectin (Felgner, et al.,supra). The plasmid pSV2-neo contains a dominant selectable marker, theneo gene from Tn5 encoding an enzyme that confers resistance to a groupof antibiotics including G418. The cells are seeded in alpha minus MEMsupplemented with 1 mg/ml G418. After 2 days, the cells are trypsinizedand seeded in hybridoma cloning plates (Greiner, Germany) in alpha minusMEM supplemented with 10, 25, or 50 ng/ml of metothrexate plus 1 mg/mlG418. After about 10-14 days single clones are trypsinized and thenseeded in 6-well petri dishes or 10 ml flasks using differentconcentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM).Clones growing at the highest concentrations of methotrexate are thentransferred to new 6-well plates containing even higher concentrationsof methotrexate (1 μM, 2 μM, 5 μM, 10 mM, 20 mM). The same procedure isrepeated until clones are obtained which grow at a concentration of100-200 μM. Expression of the desired gene product is analyzed, forinstance, by SDS-PAGE and Western blot or by reversed phase HPLCanalysis.

Example 4 Tissue Distribution of IL17RLP mRNA Expression

[0256] Northern blot analysis is carried out to examine IL17RLP geneexpression in human tissues, using methods described by, among others,Sambrook and colleagues (supra). A cDNA probe containing the entirenucleotide sequence of the IL17RLP protein (SEQ ID NO: 1) is labeledwith ³²P using the rediprime™ DNA labeling system (Amersham LifeScience), according to manufacturer's instructions. After labeling, theprobe is purified using a CHROMA SPIN-100™ column (ClontechLaboratories, Inc.), according to manufacturer's protocol numberPT1200-1. The purified labeled probe is then used to examine varioushuman tissues for IL17RLP mRNA.

[0257] Multiple Tissue Northern (MTN) blots containing various humantissues (H) or human immune system tissues (IM) are obtained fromClontech and are examined with the labeled probe using ExpressHyb™hybridization solution (Clontech) according to manufacturer's protocolnumber PT1190-1. Following hybridization and washing, the blots aremounted and exposed to film at −70° C. overnight, and films developedaccording to standard procedures.

[0258] It will be clear that the invention may be practiced otherwisethan as particularly described in the foregoing description andexamples. Numerous modifications and variations of the present inventionare possible in light of the above teachings and, therefore, are withinthe scope of the appended claims.

[0259] The entire disclosure of all publications (including patents,patent applications, journal articles, laboratory manuals, books, orother documents) cited herein are hereby incorporated by reference.

[0260] Further, the Sequence Listing submitted herewith, and theSequence Listing submitted with U.S. application Ser. No. 09/154,219,filed Sep. 16, 1998 and with U.S. Provisional Application Serial No.60/059,133, filed on Sep. 17, 1997 (to which the present applicationclaims benefit of the filing date under 35 U.S.C. § 119(e)), in bothcomputer and paper forms are hereby incorporated herein by reference intheir entireties.

1 13 1 1816 DNA Homo sapiens CDS (10)..(1287) mat_peptide (67)..(1287)sig_peptide (10)..(66) 1 gcacgagcg atg tcg ctc gtg ctg cta agc ctg gccgcg ctg tgc agg agc 51 Met Ser Leu Val Leu Leu Ser Leu Ala Ala Leu CysArg Ser -15 -10 gcc gta ccc cga gag ccg acc gtt caa tgt ggc tct gaa actggg cca 99 Ala Val Pro Arg Glu Pro Thr Val Gln Cys Gly Ser Glu Thr GlyPro -5 -1 1 5 10 tct cca gag tgg atg cta caa cat gat cta atc ccc gga gacttg agg 147 Ser Pro Glu Trp Met Leu Gln His Asp Leu Ile Pro Gly Asp LeuArg 15 20 25 gac ctc cga gta gaa cct gtt aca act agt gtt gca aca ggg gactat 195 Asp Leu Arg Val Glu Pro Val Thr Thr Ser Val Ala Thr Gly Asp Tyr30 35 40 tca att ttg atg aat gta agc tgg gta ctc cgg gca gat gcc agc atc243 Ser Ile Leu Met Asn Val Ser Trp Val Leu Arg Ala Asp Ala Ser Ile 4550 55 cgc ttg ttg aag gcc acc aag att tgt gtg acg ggc aaa agc aac ttc291 Arg Leu Leu Lys Ala Thr Lys Ile Cys Val Thr Gly Lys Ser Asn Phe 6065 70 75 cag tcc tac agc tgt gtg agg tgc aat tac aca gag gcc ttc cag act339 Gln Ser Tyr Ser Cys Val Arg Cys Asn Tyr Thr Glu Ala Phe Gln Thr 8085 90 cag acc aga ccc tct ggt ggt aaa tgg aca ttt tcc tac atc ggc ttc387 Gln Thr Arg Pro Ser Gly Gly Lys Trp Thr Phe Ser Tyr Ile Gly Phe 95100 105 cct gta gag ctg aac aca gtc tat ttc att ggg gcc cat aat att cct435 Pro Val Glu Leu Asn Thr Val Tyr Phe Ile Gly Ala His Asn Ile Pro 110115 120 aat gca aat atg aat gaa gat ggc cct tcc atg tct gtg aat ttc acc483 Asn Ala Asn Met Asn Glu Asp Gly Pro Ser Met Ser Val Asn Phe Thr 125130 135 tca cca ggc tgc cta gac cac ata atg aaa tat aaa aaa aag tgt gtc531 Ser Pro Gly Cys Leu Asp His Ile Met Lys Tyr Lys Lys Lys Cys Val 140145 150 155 aag gcc gga agc ctg tgg gat ccg aac atc act gct tgt aag aagaat 579 Lys Ala Gly Ser Leu Trp Asp Pro Asn Ile Thr Ala Cys Lys Lys Asn160 165 170 gag gag aca gta gaa gtg aac ttc aca acc act ccc ctg gga aacaga 627 Glu Glu Thr Val Glu Val Asn Phe Thr Thr Thr Pro Leu Gly Asn Arg175 180 185 tac atg gct ctt atc caa cac agc act atc atc ggg ttt tct caggtg 675 Tyr Met Ala Leu Ile Gln His Ser Thr Ile Ile Gly Phe Ser Gln Val190 195 200 ttt gag cca cac cag aag aaa caa acg cga gct tca gtg gtg attcca 723 Phe Glu Pro His Gln Lys Lys Gln Thr Arg Ala Ser Val Val Ile Pro205 210 215 gtg act ggg gat agt gaa ggt gct acg gtg cag ctg act cca tatttt 771 Val Thr Gly Asp Ser Glu Gly Ala Thr Val Gln Leu Thr Pro Tyr Phe220 225 230 235 cct act tgt ggc agc gac tgc atc cga cat aaa gga aca gttgtg ctc 819 Pro Thr Cys Gly Ser Asp Cys Ile Arg His Lys Gly Thr Val ValLeu 240 245 250 tgc cca caa aca ggc gtc cct ttc cct ctg gat aac aac aaaagc aag 867 Cys Pro Gln Thr Gly Val Pro Phe Pro Leu Asp Asn Asn Lys SerLys 255 260 265 ccg gga ggc tgg ctg cct ctc ctc ctg ctg tct ctg ctg gtggcc aca 915 Pro Gly Gly Trp Leu Pro Leu Leu Leu Leu Ser Leu Leu Val AlaThr 270 275 280 tgg gtg ctg gtg gca ggg atc tat cta atg tgg agg cac gaaagg atc 963 Trp Val Leu Val Ala Gly Ile Tyr Leu Met Trp Arg His Glu ArgIle 285 290 295 aag aag act tcc ttt tct acc acc aca cta ctg ccc ccc attaag gtt 1011 Lys Lys Thr Ser Phe Ser Thr Thr Thr Leu Leu Pro Pro Ile LysVal 300 305 310 315 ctt gtg gtt tac cca tct gaa ata tgt ttc cat cac acaatt tgt tac 1059 Leu Val Val Tyr Pro Ser Glu Ile Cys Phe His His Thr IleCys Tyr 320 325 330 ttc act gaa ttt ctt caa aac cat tgc aga agt gag gtcatc ctt gaa 1107 Phe Thr Glu Phe Leu Gln Asn His Cys Arg Ser Glu Val IleLeu Glu 335 340 345 aag tgg cag aaa aag aaa ata gca gag atg ggt cca gtgcag tgg ctt 1155 Lys Trp Gln Lys Lys Lys Ile Ala Glu Met Gly Pro Val GlnTrp Leu 350 355 360 gcc act caa aag aag gca gca gac aaa gtc gtc ttc cttctt tcc aat 1203 Ala Thr Gln Lys Lys Ala Ala Asp Lys Val Val Phe Leu LeuSer Asn 365 370 375 gac gtc aac agt gtg tgc gat ggt acc tgt ggc aag agcgag ggc agt 1251 Asp Val Asn Ser Val Cys Asp Gly Thr Cys Gly Lys Ser GluGly Ser 380 385 390 395 ccc agt gag aac tct caa gac tct tcc cct tgc ctttaaccttttc 1297 Pro Ser Glu Asn Ser Gln Asp Ser Ser Pro Cys Leu 400 405tgcagtgatc taagaagcca gattcatctg cacaaatacg tggtggtcta ctttagagag 1357attgatacaa aagacgatta caatgctctc agtgtctgcc ccaagtacca cctcatgaag 1417gatgccactg ctttctgtgc agaacttctc catgtcaagt agcaggtgtc agcaggaaaa 1477agatcacaag cctgccacga tggctgctgc tccttgtagc ccacccatga gaagcaagwg 1537accttaaagg cttcctatcc caccaattac agggaaaaaa cgtgtgatga tcctgaagct 1597tactatgcag cctacaaaca gccttagtaa ttaaaacatt ttataccaat aaaattttca 1657aatattgcta actaatgtag cattaactaa cgattggaaa ctacatttac aacttcaaag 1717ctgttttata catagaaatc aattacagtt ttaattgaaa actataacca ttttgataat 1777gcaacaataa agcatcttca gccaaaaaaa aaaaaaaaa 1816 2 426 PRT Homo sapiens 2Met Ser Leu Val Leu Leu Ser Leu Ala Ala Leu Cys Arg Ser Ala Val -15 -10-5 Pro Arg Glu Pro Thr Val Gln Cys Gly Ser Glu Thr Gly Pro Ser Pro -1 15 10 Glu Trp Met Leu Gln His Asp Leu Ile Pro Gly Asp Leu Arg Asp Leu 1520 25 Arg Val Glu Pro Val Thr Thr Ser Val Ala Thr Gly Asp Tyr Ser Ile 3035 40 45 Leu Met Asn Val Ser Trp Val Leu Arg Ala Asp Ala Ser Ile Arg Leu50 55 60 Leu Lys Ala Thr Lys Ile Cys Val Thr Gly Lys Ser Asn Phe Gln Ser65 70 75 Tyr Ser Cys Val Arg Cys Asn Tyr Thr Glu Ala Phe Gln Thr Gln Thr80 85 90 Arg Pro Ser Gly Gly Lys Trp Thr Phe Ser Tyr Ile Gly Phe Pro Val95 100 105 Glu Leu Asn Thr Val Tyr Phe Ile Gly Ala His Asn Ile Pro AsnAla 110 115 120 125 Asn Met Asn Glu Asp Gly Pro Ser Met Ser Val Asn PheThr Ser Pro 130 135 140 Gly Cys Leu Asp His Ile Met Lys Tyr Lys Lys LysCys Val Lys Ala 145 150 155 Gly Ser Leu Trp Asp Pro Asn Ile Thr Ala CysLys Lys Asn Glu Glu 160 165 170 Thr Val Glu Val Asn Phe Thr Thr Thr ProLeu Gly Asn Arg Tyr Met 175 180 185 Ala Leu Ile Gln His Ser Thr Ile IleGly Phe Ser Gln Val Phe Glu 190 195 200 205 Pro His Gln Lys Lys Gln ThrArg Ala Ser Val Val Ile Pro Val Thr 210 215 220 Gly Asp Ser Glu Gly AlaThr Val Gln Leu Thr Pro Tyr Phe Pro Thr 225 230 235 Cys Gly Ser Asp CysIle Arg His Lys Gly Thr Val Val Leu Cys Pro 240 245 250 Gln Thr Gly ValPro Phe Pro Leu Asp Asn Asn Lys Ser Lys Pro Gly 255 260 265 Gly Trp LeuPro Leu Leu Leu Leu Ser Leu Leu Val Ala Thr Trp Val 270 275 280 285 LeuVal Ala Gly Ile Tyr Leu Met Trp Arg His Glu Arg Ile Lys Lys 290 295 300Thr Ser Phe Ser Thr Thr Thr Leu Leu Pro Pro Ile Lys Val Leu Val 305 310315 Val Tyr Pro Ser Glu Ile Cys Phe His His Thr Ile Cys Tyr Phe Thr 320325 330 Glu Phe Leu Gln Asn His Cys Arg Ser Glu Val Ile Leu Glu Lys Trp335 340 345 Gln Lys Lys Lys Ile Ala Glu Met Gly Pro Val Gln Trp Leu AlaThr 350 355 360 365 Gln Lys Lys Ala Ala Asp Lys Val Val Phe Leu Leu SerAsn Asp Val 370 375 380 Asn Ser Val Cys Asp Gly Thr Cys Gly Lys Ser GluGly Ser Pro Ser 385 390 395 Glu Asn Ser Gln Asp Ser Ser Pro Cys Leu 400405 3 426 PRT Homo sapiens 3 Met Ser Leu Val Leu Leu Ser Leu Ala Ala LeuCys Arg Ser Ala Val 1 5 10 15 Pro Arg Glu Pro Thr Val Gln Cys Gly SerGlu Thr Gly Pro Ser Pro 20 25 30 Glu Trp Met Leu Gln His Asp Leu Ile ProGly Asp Leu Arg Asp Leu 35 40 45 Arg Val Glu Pro Val Thr Thr Ser Val AlaThr Gly Asp Tyr Ser Ile 50 55 60 Leu Met Asn Val Ser Trp Val Leu Arg AlaAsp Ala Ser Ile Arg Leu 65 70 75 80 Leu Lys Ala Thr Lys Ile Cys Val ThrGly Lys Ser Asn Phe Gln Ser 85 90 95 Tyr Ser Cys Val Arg Cys Asn Tyr ThrGlu Ala Phe Gln Thr Gln Thr 100 105 110 Arg Pro Ser Gly Gly Lys Trp ThrPhe Ser Tyr Ile Gly Phe Pro Val 115 120 125 Glu Leu Asn Thr Val Tyr PheIle Gly Ala His Asn Ile Pro Asn Ala 130 135 140 Asn Met Asn Glu Asp GlyPro Ser Met Ser Val Asn Phe Thr Ser Pro 145 150 155 160 Gly Cys Leu AspHis Ile Met Lys Tyr Lys Lys Lys Cys Val Lys Ala 165 170 175 Gly Ser LeuTrp Asp Pro Asn Ile Thr Ala Cys Lys Lys Asn Glu Glu 180 185 190 Thr ValGlu Val Asn Phe Thr Thr Thr Pro Leu Gly Asn Arg Tyr Met 195 200 205 AlaLeu Ile Gln His Ser Thr Ile Ile Gly Phe Ser Gln Val Phe Glu 210 215 220Pro His Gln Lys Lys Gln Thr Arg Ala Ser Val Val Ile Pro Val Thr 225 230235 240 Gly Asp Ser Glu Gly Ala Thr Val Gln Leu Thr Pro Tyr Phe Pro Thr245 250 255 Cys Gly Ser Asp Cys Ile Arg His Lys Gly Thr Val Val Leu CysPro 260 265 270 Gln Thr Gly Val Pro Phe Pro Leu Asp Asn Asn Lys Ser LysPro Gly 275 280 285 Gly Trp Leu Pro Leu Leu Leu Leu Ser Leu Leu Val AlaThr Trp Val 290 295 300 Leu Val Ala Gly Ile Tyr Leu Met Trp Arg His GluArg Ile Lys Lys 305 310 315 320 Thr Ser Phe Ser Thr Thr Thr Leu Leu ProPro Ile Lys Val Leu Val 325 330 335 Val Tyr Pro Ser Glu Ile Cys Phe HisHis Thr Ile Cys Tyr Phe Thr 340 345 350 Glu Phe Leu Gln Asn His Cys ArgSer Glu Val Ile Leu Glu Lys Trp 355 360 365 Gln Lys Lys Lys Ile Ala GluMet Gly Pro Val Gln Trp Leu Ala Thr 370 375 380 Gln Lys Lys Ala Ala AspLys Val Val Phe Leu Leu Ser Asn Asp Val 385 390 395 400 Asn Ser Val CysAsp Gly Thr Cys Gly Lys Ser Glu Gly Ser Pro Ser 405 410 415 Glu Asn SerGln Asp Ser Ser Pro Cys Leu 420 425 4 409 DNA Homo sapiens misc_feature(17) n equals a, t, g or c 4 aattcggcac gagattnatc tgcacaaata cgtggtggtctactttagag agattgatac 60 aaaanacgat tacaatgctc tcagtgtctg ccccaagtaccacctcatga aggatgccac 120 tgctttctgt gcagaacttc tccatgtnaa gtagcaggtntcagcaggaa aaagatcaca 180 agcctgccac gatggctgct gctccttgta gcccacccatgagaagcaag agaccttaaa 240 ggcttcctat cccaccaatt acagggaaaa aacgtgtgatgatcctgaag ctttactatg 300 cagcctacaa acagccttag taattaaaac atttttatacccataaaatt tttcaaatat 360 tngttaacta atngtagcat taactaangt ttgggaactacatttncaa 409 5 327 DNA Homo sapiens misc_feature (10) n equals a, t, gor c 5 aattcggcan agcccggcga tgtcgctcgt gctgctagnc tngnngcgct gtncaggagc60 gccgtacccc gagagccgac cgttcaatgt ggctctgaaa ctgggncatc tccagagtgn 120nttgctanaa catgatctaa tcccgggaga cttgagggac ctncgagtag agnctgttac 180aactagtgtt gcaacagggg actattcaan ttgatgaatg tanctgggta ctncgggnag 240ntgccancat ncgttttttg naggctnang tttngtntnn cgggnaaang tantntcagt 300cntanagtgt tngaggtgca ttaaaaa 327 6 35 DNA Homo sapiens 6 cgcccatggccgaccgttca atgtggctct gaaac 35 7 35 DNA Homo sapiens 7 cgcccatggccgaccgttca atgtggctct gaaac 35 8 34 DNA Homo sapiens 8 cgcggatccatgtcgctcgt gctgctaagc ctgg 34 9 26 DNA Homo sapiens 9 cgcggtaccccagcctcccg gcttgc 26 10 129 DNA Homo sapiens 10 gccggatccg ccaccatgaactccttctcc acaagcgcct tcggtccagt tgccttctcc 60 ctggggctgc tcctggtgttgcctgctgcc ttccctgccc cagtatgtcg ctcgtgctgc 120 taagcctgg 129 11 28 DNAHomo sapiens 11 ggccgggtac cccagcctcc cggcttgc 28 12 43 DNA Homo sapiens12 ctagccggat ccgccaccat gtcgctcgtg ctgctaagcc tgg 43 13 28 DNA Homosapiens 13 ggccgggtac cccagcctcc cggcttgc 28

What is claimed is:
 1. An isolated nucleic acid molecule nucleic acidmolecule comprising a polynucleotide having a nucleotide sequence atleast 95% identical to a sequence selected from the group consisting of:(a) a nucleotide sequence encoding the IL17RLP polypeptide having thecomplete amino acid sequence in SEQ ID NO:2 (i.e., positions −19 to 407of SEQ ID NO:2); (b) a nucleotide sequence encoding the IL17RLPpolypeptide having the complete amino acid sequence in SEQ ID NO:2excepting the N-terminal methionine (i.e., positions −18 to 407 of SEQID NO:2); (c) a nucleotide sequence encoding the predicted matureIL17RLP polypeptide having the amino acid sequence at positions 1 to 407in SEQ ID NO:2; (d) a nucleotide sequence encoding a polypeptidecomprising the predicted extracellular domain of the IL17RLP polypeptidehaving the amino acid sequence at positions 272 to 292 in SEQ ID NO:2;(e) a nucleotide sequence encoding a soluble IL17RLP polypeptide havingthe predicted extracellular and intracellular domains, but lacking thepredicted transmembrane domain; (f) a nucleotide sequence encoding theIL17RLP polypeptide having the complete amino acid sequence encoded bythe cDNA clone contained in ATCC Deposit No. 209198; (g) a nucleotidesequence encoding the IL17RLP polypeptide having the complete amino acidsequence excepting the N-terminal methionine encoded by the cDNA clonecontained in ATCC Deposit No. 209198; (h) a nucleotide sequence encodingthe mature IL17RLP polypeptide having the amino acid sequence encoded bythe cDNA clone contained in ATCC Deposit No. 209198; (i) a nucleotidesequence encoding the extracellular domain of the IL17RLP polypeptidehaving the amino acid sequence encoded by the cDNA clone contained inATCC Deposit No. 209198; and (j) a nucleotide sequence complementary toany of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g),(h) or (i) above.
 2. The nucleic acid molecule of claim 1 wherein saidpolynucleotide has the complete nucleotide sequence in FIGS. 1A, 1B, and1C (SEQ ID NO:1).
 3. The nucleic acid molecule of claim 1 wherein saidpolynucleotide has the nucleotide sequence in FIGS. 1A, 1B, and 1C (SEQID NO:1) encoding the IL17RLP polypeptide having the amino acid sequencein positions −19 to 407 of SEQ ID NO:2.
 4. The nucleic acid molecule ofclaim 1 wherein said polynucleotide has the nucleotide sequence in FIGS.1A, 1B, and 1C (SEQ ID NO:1) encoding the IL17RLP polypeptide having theamino acid sequence in positions −18 to 407 of SEQ ID NO:2.
 5. Thenucleic acid molecule of claim 1 wherein said polynucleotide has thenucleotide sequence in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) encoding themature IL17RLP polypeptide having the amino acid sequence from about 1to about 407 in SEQ ID NO:2.
 6. The nucleic acid molecule of claim 1wherein said polynucleotide has the nucleotide sequence in FIGS. 1A, 1B,and 1C (SEQ ID NO:1) encoding the extracellular domain of the IL17RLPpolypeptide having the amino acid sequence from about 1 to about 407 inSEQ ID NO:2.
 7. An isolated nucleic acid molecule comprising apolynucleotide having a nucleotide sequence at least 95% identical to asequence selected from the group consisting of: (a) a nucleotidesequence encoding a polypeptide comprising the amino acid sequence ofresidues n-407 of SEQ ID NO:2, where n is an integer in the range of−19-5; (b) a nucleotide sequence encoding a polypeptide comprising theamino acid sequence of residues −19-m of SEQ ID NO:2, where m is aninteger in the range of 340-407; (c) a nucleotide sequence encoding apolypeptide having the amino acid sequence consisting of residues n-m ofSEQ ID NO:2, where n and m are integers as defined respectively in (a)and (b) above; and (d) a nucleotide sequence encoding a polypeptideconsisting of a portion of the complete IL17RLP amino acid sequenceencoded by the cDNA clone contained in ATCC Deposit No. 209198 whereinsaid portion excludes from 1 to about 23 amino acids from the aminoterminus of said complete amino acid sequence encoded by the cDNA clonecontained in ATCC Deposit No. 209198; (e) a nucleotide sequence encodinga polypeptide consisting of a portion of the complete IL17RLP amino acidsequence encoded by the cDNA clone contained in ATCC Deposit No. 209198wherein said portion excludes from 1 to about 67 amino acids from thecarboxy terminus of said complete amino acid sequence encoded by thecDNA clone contained in ATCC Deposit No. 209198; and (f) a nucleotidesequence encoding a polypeptide consisting of a portion of the completeIL17RLP amino acid sequence encoded by the cDNA clone contained in ATCCDeposit No. 209198 wherein said portion include a combination of any ofthe amino terminal and carboxy terminal deletions in (d) and (e), above.8. The nucleic acid molecule of claim 1 wherein said polynucleotide hasthe complete nucleotide sequence of the cDNA clone contained in ATCCDeposit No.
 209198. 9. The nucleic acid molecule of claim 1 wherein saidpolynucleotide has the nucleotide sequence encoding the IL17RLPpolypeptide having the complete-amino acid sequence excepting theN-terminal methionine encoded by the cDNA clone contained in ATCCDeposit No.
 209198. 10. The nucleic acid molecule of claim 1 whereinsaid polynucleotide has the nucleotide sequence encoding the matureIL17RLP polypeptide having the amino acid sequence encoded by the cDNAclone contained in ATCC Deposit No.
 209198. 11. The nucleic acidmolecule of claim 1 wherein said polynucleotide has the nucleotidesequence encoding the extracellular domain of the IL17RLP polypeptidehaving the amino acid sequence encoded by the cDNA clone contained inATCC Deposit No.
 209198. 12. An isolated nucleic acid moleculecomprising a polynucleotide which hybridizes under stringenthybridization conditions to a polynucleotide having a nucleotidesequence identical to a nucleotide sequence in (a), (b), (c), (d), (e),(f), (g), (h), (i) or (j) of claim 1 wherein said polynucleotide whichhybridizes does not hybridize under stringent hybridization conditionsto a polynucleotide having a nucleotide sequence consisting of only Aresidues or of only T residues.
 13. An isolated nucleic acid moleculecomprising a polynucleotide which encodes the amino acid sequence of anepitope-bearing portion of a IL17RLP polypeptide having an amino acidsequence in (a), (b), (c), (d), (e), (f), (g), (h) or (i) of claim 1.14. The isolated nucleic acid molecule of claim 13, which encodes anepitope-bearing portion of a IL17RLP polypeptide wherein the amino acidsequence of said portion is selected from the group of sequences in SEQID NO:2 consisting of: about Ser-14 to about Val-22, about Cys-24 toabout Pro-32, about Ile-41 to about Arg-49, about Thr-89 to aboutVal-97, about Thr-110 to about Lys-118, about Ala-144 to about Ser-152,about Thr-240 to about Val-248, about Gly-258 to about Thr-267, aboutLeu-280 to about Gly-288, about Cys-404 to about Glu-412, about Pro-415to about Ser-423, about Gly-409 to about Glu-417, and about Cys-404 toabout Leu-426.
 15. A method for making a recombinant vector comprisinginserting an isolated nucleic acid molecule of claim 1 into a vector.16. A recombinant vector produced by the method of claim
 15. 17. Amethod of making a recombinant host cell comprising introducing therecombinant vector of claim 16 into a host cell.
 18. A recombinant hostcell produced by the method of claim
 17. 19. A recombinant method forproducing a IL17RLP polypeptide, comprising culturing the recombinanthost cell of claim 18 under conditions such that said polypeptide isexpressed and recovering said polypeptide.
 20. An isolated IL17RLPpolypeptide comprising an amino acid sequence at least 95% identical toa sequence selected from the group consisting of: (a) the amino acidsequence of the full-length IL17RLP polypeptide having the completeamino acid sequence shown in SEQ ID NO:2 (i.e., positions −19 to 407 ofSEQ ID NO:2); (b) the amino acid sequence of the full-length IL17RLPpolypeptide having the complete amino acid sequence shown in SEQ ID NO:2excepting the N-terminal methionine (i.e., positions −18 to 407 of SEQID NO:2); (c) the amino acid sequence of the mature IL17RLP polypeptidehaving the complete amino acid sequence shown in SEQ ID NO:2 (i.e.,positions 1 to 407 of SEQ ID NO:2); (d) the amino acid sequence of thepredicted extracellular domain of the IL17RLP polypeptide having thecomplete amino acid sequence shown in SEQ ID NO:2 (i.e., positions 1 to271 of SEQ ID NO:2); (e) the amino acid sequence of a soluble IL17RLPpolypeptide having the predicted extracellular and intracellulardomains, but lacking the predicted transmembrane domain; (f) thecomplete amino acid sequence encoded by the cDNA clone contained in theATCC Deposit No. 209198; (g) the complete amino acid sequence exceptingthe N-terminal methionine encoded by the cDNA clone contained in theATCC Deposit No. 209198; (h) the complete amino acid sequence of themature IL17RLP encoded by the cDNA clone contained in the ATCC DepositNo. 209198, and; (i) the complete amino acid sequence of theextracellular domain of the IL17RLP encoded by the cDNA clone containedin the ATCC Deposit No.
 209198. 21. An isolated polypeptide comprisingan epitope-bearing portion of the IL17RLP protein, wherein said portionis selected from the group consisting of: a polypeptide comprising aminoacid residues from about Ser-14 to about Val-22 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Cys-24 to aboutPro-32 in SEQ ID NO:2, a polypeptide comprising amino acid residues fromabout Ile-41 to about Arg-49 in SEQ ID NO:2, a polypeptide comprisingamino acid residues from about Thr-89 to about Val-97 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Thr-110 to aboutLys-118 in SEQ ID NO:2, a polypeptide comprising amino acid residuesfrom about Ala-144 to about Ser-152 in SEQ ID NO:2, a polypeptidecomprising amino acid residues from about Thr-240 to about Val-248 inSEQ ID NO:2, a polypeptide comprising amino acid residues from aboutGly-258 to about Thr-267 in SEQ ID NO:2, a polypeptide comprising aminoacid residues from about Leu-280 to about Gly-288 in SEQ ID NO:2, apolypeptide comprising amino acid residues from about Cys-404 to aboutGlu-412 in SEQ ID NO:2, a polypeptide comprising amino acid residuesfrom about Pro-415 to about Ser-423 in SEQ ID NO:2, a polypeptidecomprising amino acid residues from about Gly-409 to about Glu-417 inSEQ ID NO:2, and a polypeptide comprising amino acid residues from aboutCys-404 to about Leu-426
 22. An isolated antibody that bindsspecifically to a IL17RLP polypeptide of claim
 20. 23. An isolatednucleic acid molecule comprising a polynucleotide having a sequence atleast 95% identical to a sequence selected from the group consisting of:(a) the nucleotide sequence of SEQ ID NO:4); (b) the nucleotide sequenceof SEQ ID NO:5); (c) the nucleotide sequence of a portion of thesequence shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) wherein saidportion comprises at least 50 contiguous nucleotides from nucleotide 50to nucleotide 650; (d) the nucleotide sequence of a portion of thesequence shown in FIGS. 1A, 1B, and 1C (SEQ ID NO:1) wherein saidportion consists of nucleotides 50-1800, 100-1800, 200-1800, 300-1800,400-1800, 500-1800, 600-1800, 50-650, 100-650, 200-650, 300-650,400-650, 500-650, 50-500, 100-500, 200-500, 300-500, 400-500, 50-400,100-400, 200-400, 300-400, 50-300, 100-300, 200-300, 50-200, 100-200,and 50-100; and (e) a nucleotide sequence complementary to any of thenucleotide sequences in (a), (b), (c) or (d) above.